Ex Parte Palmer et alDownload PDFPatent Trials and Appeals BoardMay 13, 201912985579 - (D) (P.T.A.B. May. 13, 2019) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/985,579 01/06/2011 45511 7590 05/15/2019 Baker Hostetler Cira Centre, 12th Floor 2929 Arch Street Philadelphia, PA 19104-2891 FIRST NAMED INVENTOR Peter Albert Palmer UNITED STATES DEPARTMENT OF COMMERCE United States Patent and Trademark Office Address: COMMISSIONER FOR PATENTS P.O. Box 1450 Alexandria, Virginia 22313-1450 www .uspto.gov ATTORNEY DOCKET NO. CONFIRMATION NO. 103693.000736 4616 EXAMINER KLINKEL, KORTNEY L ART UNIT PAPER NUMBER 3649 NOTIFICATION DATE DELIVERY MODE 05/15/2019 ELECTRONIC Please find below and/or attached an Office communication concerning this application or proceeding. The time period for reply, if any, is set in the attached communication. Notice of the Office communication was sent electronically on above-indicated "Notification Date" to the following e-mail address(es): eofficemonitor@bakerlaw.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PETER ALBERT PALMER and IV AN DAVID HORAK Appeal2017-009075 Application 12/985,579 1 Technology Center 1600 Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. Opinion for the Board filed by Administrative Patent Judge TOWNSEND. Opinion Dissenting filed by Administrative Patent Judge PRATS. TOWNSEND, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to a method of treating advanced breast cancer, which have been rejected as obvious. We have jurisdiction under 35 U.S.C. § 6(b). We affirm. 1 Appellants identify the real party in interest as Janssen Pharmaceutica N.V. (Appeal Br. 1.) Appeal2017-009075 Application 12/985,579 STATEMENT OF THE CASE "Breast cancer is the most common female malignancy and the main cause of death from cancer in women." (Spec. 2.) Appellants' invention is concerned with using a famesyl protein transferase inhibitor for treating advanced cancer. (Spec. 14.) The famesyl transferase inhibitors are compounds known in the prior art. (Id. at 2-14 (identifying prior art disclosing preparation of famesyl protein transferase inhibitors of formulas (I), (II), (III), (IV), (V), (VI), (VII), (VIII) or (IX).) Claims 16, 17, 20, 24, and 35 are on appeal.2 Claim 16 is representative and reads as follows: 16. A method of treating advanced breast cancer in a mammal comprising administering orally to said mammal the compound ( + )-6-[ amino( 4-chlorophenyl)(l-methyl-lH-imidazol-5- y 1 )methy 1 ]-4-( 3-chl orop heny 1 )-1-me thy 1-2 ( 1 H)-quino linone or a pharmaceutically acceptable acid addition salt thereof, in a dosage amount of 300mg twice daily, for a period of at least 3 months. (Appeal Br. 6.) 2 Claims 21-23 and 25-34 are pending but stand withdrawn from consideration. (Appeal Br. 2.) 2 Appeal2017-009075 Application 12/985,579 The following ground of rejection by the Examiner is before us on review: Claims 16, 17, 20, 24, and 35 under 35 U.S.C. § 103(a) as unpatentable over the Zujewski Abstract,3 as evidenced by the Zujewski Article,4 and Bishop.5 DISCUSSION I The Examiner finds, and there is no dispute by Appellants, that the Zujewski Abstract teaches oral administration of famesyl-transferase inhibitor Rl 15777 twice daily for the treatment of advanced breast cancer. (Final Action 6; See Appeal Br. 2-4.) The Examiner contends that the Zujewski Article establishes that Rl 15777 is inherently ( + )-6-[ amino( 4- chlorophenyl)( l -methyl-IH-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)- l - methyl-2( l H)-quinolinone, whether recognized by one of skill in the art. (Final Action 6, 10; Ans. 8.) The Examiner recognizes that the article is not prior art as of Appellants' foreign priority date, February 4, 2000, but contends that this reference is not relied upon as prior art, but only to establish, as a matter of fact, that the compound having code name Rl 1577 3 Zujewski et al., # 1848 Phase I trial of farnesyl-transferase inhibitor, RI 15777, 39 Proc. Am. Assoc. Cancer Res., 270 (1998). 4 Zujewski et al., Phase I and Pharmacokinetic Study of Farnesyl Protein Transferase Inhibitor RI 1577 in Advanced Cancer, 18(4) J. Clin. Oncol., 927-941 (2000). 5 Bishop et al., US 6,096,757, issued Aug. 1, 2000. 3 Appeal2017-009075 Application 12/985,579 inherently has the chemical structure of the compound set forth in claim 16. (Id.) Appellants do not dispute that Rl 15777 is inherently ( + )-6-[ amino( 4- chlorophenyl)( l -methyl-IH-imidazol-5-yl)methyl]-4-(3-chloro-phenyl)- l - methyl-2( l H)-quinolinone. (Appeal Br. 2-4; Reply Br. 2-3.) Appellants dispute, however, that one of ordinary skill in the art "had any knowledge of the chemical structure of Rl 15777 or how to obtain it" at the time of Appellants' effective filing date, February 4, 2000, from "the publications that were available to those of ordinary skill in the art." (Appeal Br. 3-4.) Appellants explain that the Zujewski Article published after Appellants' priority date, and, thus, "is not representative of what those of ordinary skill knew at the time of Appellants' invention." (Id. at 3.) Appellants explain that the "person of ordinary skill who had read the Zujewski Abstract when Appellants' filed their priority application would have had no idea of what the drug [Rl 15777] was or how, if it all, it related to the claimed subject methods." (Id.) Appellants assert "that the information that the [prior art] publications provide would have been insufficient for a person of ordinary skill to prepare or otherwise obtain the chemical compound that the claimed methods require," i.e., the Examiner has not established that the prior art enables the claimed method. (Id.) Accordingly, argue Appellants, the Examiner's obviousness rejection is improper. (Id. ( citing Beckman Instruments, Inc. v. LKB Produktor AB, 892 F.2d 1547, 1550 (Fed. Cir. 1989)).) We do not find Appellants' argument persuasive for the reasons that follow. 4 Appeal2017-009075 Application 12/985,579 The Chemical Structure of RI 15777 is Inherent as is its Chemical Name We assume for purposes of this Appeal that Appellants are entitled to rely on the foreign priority application date of February 4, 2000 as their effective filing date, as the Examiner has not asserted otherwise. Appellants argue that the Zujewski Article post-dates February 4, 2000 and cannot be relied upon to establish what was known to one of ordinary skill in the art with respect to the chemical structure of Rl 15777 as of February 4, 2000. (Appeal Br. 3 ("In re Payne, 203 U.S.P.Q. 245, 255 (C.C.P.A. 1979) (references relied upon to support rejection under § 103 must place the claimed invention in the possession of the public))".) We disagree. It is well-established that post-filing date references can be relied upon to establish the characteristics of a prior art product. In re Wilson, 311 F.2d 266, 268-69 (CCPA 1962)(finding it appropriate for the Board to have relied on a post-filing date publication for a discussion of the properties of polyurethane foam products made by the processes of the prior art). Thus, that the "identity" by way of chemical structure of Rl 15777 was not provided in the Zujewski Abstract (Appeal Br. 3) is not dispositive of whether the Examiner has established a prima facie case of obviousness. A patent cannot claim something that already exists. In re Crish, 393 F.3d 1253, 1368 (Fed. Cir. 2004) ("However, just as the discovery of properties of a known material does not make it novel, the identification and characterization of a prior art material also does not make it novel."); see also In re Baxter-Travenol Labs., 952 F.2d 388, 392 (Fed. Cir. 1991) ("Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention."). "Inherency places subject matter in the public domain as well as an express disclosure." Schering Corp. v. Geneva 5 Appeal2017-009075 Application 12/985,579 Pharms., Inc., 339 F.3d 1373, 1379 (Fed. Cir. 2003). Indeed, "inherency operates to anticipate entire inventions as well as single limitations within an invention." Id. at 1380. There can be no dispute that Rl 15777 is a drug compound. It is described in the Zujewski Abstract as a farnesyl-transferase inhibitor that is undergoing human phase I study. (Zujewski Abstract.) There also can be no dispute that this drug compound has a chemical structure. Our reviewing court has explained that a nucleotide sequence is the identity of the structure of a gene. Crish, 393 F.3d at 1368. Analogously, the chemical structure of compound Rll 5777 is the identity of that compound. The chemical structure of the compound Rl 15777 is inseparable from its identity. Id. 6 Here too the structure of the chemical compound Rl 15777 is characteristic of that compound no matter by what name it is called. It is certainly true that the chemical structure of any chemical compound can be drawn out with relative ease when it is identified with the naming scheme of the International Union of Pure and Applied Chemistry ("IUP AC"). However, there is a structure for any chemical compound regardless of whether it is called by its IUP AC name. Moreover, the chemical name for a chemical compound can be discerned from its chemical structure. 6 Our dissenting colleague notes that the Zujewski Abstract "provides no structural details" of Rl 15777 and notes that "it is undisputed that the Zujewski Abstract, even when viewed in combination with Bishop, does not provide any specific suggestion that Rl 15777 might be the compound recited in Appellants' claim 16." (Dissent at 2.) While true, neither fact is material to whether the Zujewski Abstract, nevertheless, inherently discloses the claimed compound. 6 Appeal2017-009075 Application 12/985,579 Importantly, here, Appellants do not argue that the chemical structure of Rl 15777 changed over time. Notably, David Horak, who is one of the named inventors, is an author on both the Zujewski Abstract and the Zujewski Article. If the chemical structure of the compound identified by the code name Rl 15777 did change, one would have expected inventor Horak to be in possession of such knowledge and to have provided that information during prosecution here. Appellants have not pointed to any such evidence. (See, Ans. 9 ("There is no evidence to the contrary [that Rl 15777 described in the Zujewski Abstract is not the claimed compound].").) Indeed, Appellants do not dispute in this appeal that Rl 15777 is inherently (+)-6-[amino(4-chlorophenyl)(l-methyl-IH-imidazol- 5-yl)methyl]-4-(3-chloro-phenyl)-l-methyl-2(1 H)-quinolinone. (Appeal Br. 2-4; Reply Br. 2-3.) And, the inherency of this fact is borne out by the Zujewski Article Figure 1 depicted below. (See Ans. 8.) Cl Cl I 0 fig 1. Chemkcil $1rudute cf Rl 15777 or {B)-6-laminci!4-chloropltenyll{1- methyl- l H-imidazol-5yl)melhyll-4-(3-chlorophenyl}-1-methyl-2(1H}-quinoli- no~. (Zujewski Article 929). The figure above provides the "[ c ]hemical structure of Rl 15777." (Id.) That structure is the chemical compound recited in claim 16 on appeal here. 7 Appeal2017-009075 Application 12/985,579 That the Zujewski Article is a post-filing date article (Appeal Br. 3) is of no moment. That is because, as discussed above, the fact of the chemical Rl 15777's structure, which is its identity, existed as of the existence of Rl 15777. See Crish, 393 F.3d at 1368. It is permissible to consider post- filing date publications to demonstrate extant characteristics of known prior art products. Wilson, 311 F.2d at 268-269 (relying on post-filing date evidence "not as prior art, but as a 'teaching reference' to show a fact with respect to polyurethane foams" described in the prior art). Thus, we agree with the Examiner (Ans. 9), that Rl 15777 described by the prior art Zujewski Abstract is inherently the compound claimed, as verified by the Zujewski Article. 7 Moreover, as the Examiner properly noted (Ans. 8), there is no requirement that the public had to have recognized the chemical structure ( or the corresponding chemical name) of compound Rl 15777 in the prior art for the Zujewski Abstract to anticipate or render obvious the claimed invention. "[I]nherent anticipation does not require that a person of ordinary skill in the art at the time would have recognized the inherent disclosure." Abbott Labs. v. Baxter Pharm. Prods., Inc., 471 F.3d 1363, 1368 (Fed. Cir. 2006); see also Atlas Powder Co. v. IRECO Inc., 190 F.3d 1342, 1349 (Fed. Cir. 1999) ("Insufficient prior understanding of the inherent properties of a known 7 Our dissenting colleague contends that we improperly rely on the Zujewski Article, which is not prior art, to identify Rl 15777 as being the claimed compound. (Dissent at 3.) However, as just discussed, the structure ofRl 15777, by which one can discern its IUPAC chemical name, is a factual characteristic of that compound that exists regardless of whether it is so stated in the Zujewski Abstract. The Zujewski Article merely illustrates that extant factual characteristic. 8 Appeal2017-009075 Application 12/985,579 composition does not defeat a finding of anticipation."). All that is required is the missing information necessarily be present. Abbott Labs., 471 F.3d at 1368. Thus, for example, it was found that the metabolite of loratadine known as DCL was anticipated by prior art that neither disclosed its name or the chemical structure of DCL, but disclosed that loratidine was administered to humans. Schering Corp. v. Geneva Pharms., 339 F.3d 1373, 1378-79 (Fed. Cir. 2003). The court explained that, "the prior art supplie[ d] no express description of any part of the claimed subject matter ... ;" the prior art did "not disclose any compound that is identifiable as DCL." Id. at 1378; see also id. 1379 ("DCL[] is not described by the prior '233 patent"). But that was unimportant, said the court, "[b Jecause inherency places subject matter in the public domain as well as an express disclosure[.]" Id. As the court further noted: The extent of the inherent disclosure does not limit its anticipatory effect. In general, a limitation or the entire invention is inherent and in the public domain if it is the "natural result flowing from" the explicit disclosure of the prior art. Id. The court noted that "DCL forms in readily detectable amounts as shown by the extensive record evidence of testing done on humans to verify the formation ofDCL upon ingestion of loratadine." Id. As we just explained, the chemical structure and chemical name of Rl 15777 is necessarily the chemical structure disclosed in the Zujewski Article and the chemical name recited in claim 16, irrespective of whether one of ordinary skill in the art recognized it at the time. The extent of the Zujewski Abstract' s inherent disclosure "does not limit its anticipatory effect." Id. In short, it is simply not relevant to the inherency of the 9 Appeal2017-009075 Application 12/985,579 disclosure of the Zujewski Abstract under the current law, that a "person of ordinary skill who had read the Zujewski Abstract when Appellants' filed their priority application would have had no idea of what the drug [Rl 15777] was or how, if it all, it related to the claimed subject methods" (Appeal Br. 3). The chemical structure and chemical name of Rl 15777 are inherent to it. The Prior Art Enables One of Ordinary Skill in the Art to Make RI 15777 Appellants argue that one "of ordinary skill in the art [would not have been able] to prepare or otherwise obtain the chemical compound that the claimed methods require," from "the information that the publications provide" and thus, "would not have been able to practice any of Appellants' claimed methods." (Reply Br. 1.) We do not find this argument persuasive. It is true that "[i]n order to render a claimed apparatus or method obvious, the prior art must enable one skilled in the art to make and use the apparatus or method." Beckman Instruments, Inc. v. LKB Produktor AB, 892 F.2d 1547, 1551 (Fed. Cir. 1989). However, we note that separate disclosures may properly support the enablement question. See In re Payne, 606 F.3d 303,315 (CCPA 1979) (explaining that it is permissible to rely on a separate reference to establish enablement of how to make a compound disclosed in the prior art); see also Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246 F.3d 1368, 1379 (2001) (noting that relying on Applicant admissions during prosecution can support a finding that the prior art is enabling of the claimed invention). 8 In other words, that the Zujewski 8 We note that enablement of an anticipatory disclosure in a prior art reference may even be demonstrated by a post-filing date reference. See Bristol-Myers Squibb Co. v. Ben Venue Laboratories, Inc., 246 F.3d 1368, 10 Appeal2017-009075 Application 12/985,579 Abstract itself does not describe how to make Rl 15777, and simply identifies the compound by this code name (Reply Br. 2), is not determinative of whether one of ordinary skill in the art would have known how to make that compound given the present record. Moreover, we must "start first with the knowledge that a relevant skilled artisan would have in this case." In re Morsa, 803 F.3d 1374, 1377 (Fed. Cir. 2015). Appellants do not contest that one of ordinary skill in the art would not have known how to make the chemical structure that is Rl 15777 as of the effective filing date. Indeed, they could not. Appellants' Specification states that "W0-97 /2171 describes the preparation, formulation and pharmaceutical properties of famesyl protein transferase inhibiting (imidazoly-5-yl)methyl-2-quinolinone derivatives of formulas (I) . . . . " (Spec. 2.) Appellants' Specification further indicates that the claimed compound, i.e., ( + )-6-[ amino( 4-chlorophenyl)(l-methyl-1H-imidazol-5- yl)methyl]-4-(3-chlorophenyl)-l-methyl-2(1H)-quinolinone, that is used in the claimed method, is described by formula (I) of the Specification. (Spec. 17:20-19:8.) The Specification even notes that this compound is compound 75 of table 1 of WO 97/21701 (id. at 19:6-8), and that this prior art reference discloses how to prepare pharmaceutical compositions of the compounds of formula (1) (id. at 23:20-24). 9 Thus, Appellants' Specification admits that 13 79 (2001) ( analyzing cases in arriving at the conclusion that it is appropriate to rely on pre- or post-filing date references in determining whether a claim limitation would have been enabled to one of skill in the art more than one year prior to the claims earliest filing date). 9 WO 97/21701 is an international patent application that was published June 19, 1997. Thus, it is undisputedly prior art. Not only does WO 97/21701 identify the claimed compound in terms of its chemical 11 Appeal2017-009075 Application 12/985,579 the state of the art at the time the invention was made enabled making the claimed compound. See In re Morsa, 803 F.3d at 1377 ("[C]onsidering that the PMA reference discloses each claim limitation, and that the application's specification indicates that a person of ordinary skill in the art is capable of programming the invention, the Board's conclusion that the PMA reference is enabling is correct."). In light of the foregoing, it is indisputable that one of ordinary skill in the art would have known how to make the chemical structure that is Rl 15777 based on the prior art, despite the Zujewski Abstract' s silence, itself, on the matter. Consequently, we find the prior art "enables access to" (Reply Br. 2) the structure that is Rl 15777. 10 During oral argument, Appellants directed our attention to Endo Pharmaceuticals Solutions v. Custopharm, 894 F.3d 1374 (Fed. Cir. 2018), structure in Table 1, it also provides a description of making compound 75. (WO 97/21701, 26:21-31 (Example B.8b)). Additionally, it teaches that the compounds can be used to inhibit tumor growth in breast carcinoma. (Id. 17:1-15.) 10 We note further the American Association for Cancer Research ("AACR") policy at the time that the Zujewski Abstract was published, concerning the availability of materials stated: "It is understood that by publishing any work in Cancer Research the authors agree to make freely available to other academic researchers any of the cells, clones of cells or DNA or antibodies, etc. that were used in the research reported and that are not available from commercial supplier." Retrieved from https://web.archive.org/web/1998013010 l 733/http://www.aacr.org/caninst.h tm. We understand the chemical compound Rl 15777 referred to in the Zujewski Abstract and used in the research reported to fall within the "etc." category of material to be made freely available according to the AACR policy. Thus, contrary to Appellants' assertion (Reply Br. 1), one of ordinary skill in the art would have been able to "obtain the chemical compound that the claimed methods require" between March 1998 and March 2004, i.e., before the asserted priority date. 12 Appeal2017-009075 Application 12/985,579 contending that the outcome in that case requires a similar conclusion on non-enablement here. We disagree. In Endo, the claims at issue were directed to both a composition that included a particular drug in a vehicle that included castor oil and a co- solvent, and a method of using that composition. 894 F.3d at 1377. The district court found that three articles described small clinical studies involving the claimed drug as well as provided pharmacokinetic performance data, and noted that the "the parties agree[ d] that the Articles do not disclose or describe the use of a co-solvent" despite the fact that "the actual formulation of the vehicle used in the studies" included the claimed co-solvent. Id. at 1378, 1381. The fact that it was undisputed that the Articles did not disclose use of a co-solvent stands in stark contrast to the facts before us, where there is absolutely no dispute that the Zujewski Abstract discloses the use of Rl 15777. What is not "disclosed" here is the inherent structure of Rl 15777, the undisputed identity of that chemical compound. What was not disclosed in Endo, was not proved to be inherent as will be explained below. The district court determined that the evidence just described was insufficient to establish the Articles inherently disclosed a formulation that included a co-solvent. Id. at 1378. The Federal Circuit affirmed the finding that there was not clear and convincing evidence that the claimed co-solvent was necessarily and inevitably present in the formulation described in the Articles. (Id. at 1381-82.) The Federal Circuit explained that "the Articles failed to disclose that the composition's vehicle formulation included" a co- solvent, "[ a ]nd there was no evidence in the record that a skilled artisan could determine the non-disclosed vehicle formulation based on the reported 13 Appeal2017-009075 Application 12/985,579 phannacokinetic performance profile, or that the non-disclosed vehicle formulation was necessarily a feature of the ... injection studied in the Articles." Id. at 1383. The Federal Circuit explained that no argument was made that the pharmacokinetic performance "can only be attributed to the claimed vehicle formulation." Id. at 1382. The Federal Circuit found "the record [ to be] devoid of any proof that only one vehicle formulation - the claimed vehicle formulation - [ could] be used to achieve the pharmacokinetic performance reported in the Articles." Id. at 1383. Here, in stark contrast, the drug that was described in the Zujewski Abstract as Rl 15777 is undisputedly the compound recited by the chemical named in claim 16. That chemical name and the structure of that chemical is the identity of Rl 15777 irrespective of the fact that it was not explicitly stated in the abstract and is "inherent" to compound Rl 15777. We conclude that failing to find the Zujewski Abstract an invalidating disclosure of the chemical compound that one of ordinary skill in the art undisputedly knew how to make at the time the priority application was filed here would incentivize withholding compound information from the public for years by only referring to codenames and "would materially retard the progress of science and the useful arts," Pennockv. Dialogue, 27 US 1, 19 (1829). We conclude that would not be good policy. For the reasons discussed, we find that the Zujewski Abstract is anticipatory prior art, as evidenced by Appellants' admissions in the Specification that the prior art enables how to make the specific chemical compound claimed to be used in the method of claim 16. 14 Appeal2017-009075 Application 12/985,579 II Appellants also argue in footnote 3 of their opening brief that "[t]he rejection for alleged obviousness is also improper because cited references fail to teach or suggest the claimed administration period of three months." (Appeal Br. 4, n.3.) The Examiner explains that the Zujewski Abstract teaches administration of Rl 15777 "orally twice daily (po BID) for 10 doses followed by 9 days of rest." (Final Action 6.) Thus, it "reads on continuous administration on a daily basis for a series of days." (Id.) The Examiner further notes that the Zujewski Abstract teaches "that 15 patients have been enrolled over 5 dose levels and a total of 43 cycles have been administered." (Id.) The Examiner contends that even though it is not clear whether "each patient has received 43 cycles or if the 43 cycles is distributed across the 15 patients ... [, but e ]ither way, the treatment period is several weeks and there is no mention of an endpoint." (Id.; see also Ans. 10 ("Either way, the treatment period is several weeks ( a range of over 40 days if each patient is given the average number of cycles.)".) The Examiner agrees that the Zujewski Abstract does not teach dosing for 3 months, but Bishop "teaches continuous dosing as well as intermittent therapy such as one week out of three weeks or three out of four weeks ( col. 14 7, lines 12-14. )" (Final Action 7; see also Ans.11 (noting that Bishop provides examples in which the dosing period was several weeks).) The Examiner concludes "whereas the combination of references fails to explicitly teach a treatment period of at least 3 months, both teach treatment periods of several weeks and it would be obvious to optimize the treatment 15 Appeal2017-009075 Application 12/985,579 period depending on the severity of the cancer, side effects, etc." (Id. at 8.) We agree with the Examiner's findings and conclusion. Assuming as the Examiner did, that in one conservative interpretation of the Zujewski Abstract, the 43 cycles were distributed over the 15 patients, meaning that each patient underwent 3 cycles. Each cycle is a treatment period of 14 days: 5 days of receiving the drug and 9 days off. Thus, the Zujewski Abstract conservatively teaches 3 two week treatment periods for a total of six weeks of treatment. Moreover, as the Examiner also notes, Bishop teaches a one week out of three weeks or three out of four weeks treatment scheme. (Bishop 147:12-14.) Thus, we agree with the Examiner that the references teach treatment over several weeks. 11 Appellants admit that the Zujewski Abstract "discloses that 43 cycles of 5 days of treatment followed by 9 days were administered during their study" and that 15 patients were treated. (Appeal Br. 3, n. 3.) Appellants also admit that Bishop "involve[ s] at most a treatment period of 32 days" and also provides a prophetic example continuous and intermittent dosing. (Id.) Appellants' dispute with the Examiner's rejection is that the references do not teach the length of treatment claimed, and Bishop "provides no guidance for one of ordinary skill to use a treatment regimen lasting three months." (Id.) We do not find this argument overcomes the Examiner's rejection, where the art provides guidance on intermittent dosing for 11 The Examiner expounds on an "overlapping" dosing range in the answer. (Ans. 10-11.) Appellants take issue with the Examiner's overlapping range as it relates to the Zujewski Abstract teaching 20 months of treatment. (Reply Br. 3.) We do not rely on the possible 20 month length of treatment in the Zujewski Abstract in affirming the Examiner's rejection, as it is not necessary to do so. 16 Appeal2017-009075 Application 12/985,579 treatment over a period of weeks. One of ordinary skill in the art would find guidance in those teachings as to how to continue treatment for as long as needed to achieve efficacy. We agree with the Examiner, and Appellants do not dispute, that "it would be obvious to optimize the treatment period depending on the severity of the cancer, side effects, etc." (Final Action 8; Ans. 11.) As the Examiner noted, "Appellant has not demonstrated that the claimed twice daily dose of 300 mg for at least 3 months is somehow critical or unexpected and therefore the claims remain prim a facie obvious over the combined teachings of the prior art." (Ans. 11.) We agree. Claims 17, 20, 24, and 35 have not been argued separately and therefore fall with claim 16. 37 C.F.R. § 41.37(c)(l)(iv). SUMMARY We affirm the rejection of claims 16, 17, 20, 24, and 35 under 35 U.S.C. § 103(a) as unpatentable over Zujewski Abstract, as evidenced by Zujewski Article, and Bishop. TIME PERIOD FOR RESPONSE No time period for taking any subsequent action in connection with this appeal may be extended under 37 C.F.R. § l .136(a). AFFIRMED 17 UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte PETER ALBERT PALMER and IV AN DAVID HORAK Appeal2017-009075 Application 12/985,579 Technology Center 1600 Before FRANCISCO C. PRATS, ULRIKE W. JENKS, and RACHEL H. TOWNSEND, Administrative Patent Judges. PRATS, Administrative Patent Judge, dissenting. I respectfully dissent. In my view, the Examiner's rejection of claims 16, 17, 20, 24, and 35 for obviousness over the Zujewski Abstract, as evidenced by the Zujewski Article, and Bishop, should be reversed. Claim 16, the only independent claim subject to that rejection, recites treating advanced breast cancer by orally administering, to a mammal, a specific compound: ( + )-6-[ amino( 4- chlorophenyl)(l-methyl-lH-imidazol- 5-yl)methyl]-4-(3-chlorophenyl)-l-methyl- 2(1H)-quinolinone, or a pharmaceutically acceptable acid addition salt thereof. Appeal Br. 6. Thus, as Appellants contend, to render the process recited in claim 16 obvious, the prior art cited in the rejection must place the claim-recited compound into the hands of the public. See In re Payne, 606 F.2d 303, 314 Appeal2017-009075 Application 12/985,579 (CCPA 1979) ("References relied upon to support a rejection under 35 USC § 103 must provide an enabling disclosure, i.e., they must place the claimed invention in the possession of the public. . . . "An invention is not possessed absent some known or obvious way to make it.") (emphasis added; citation and internal quotes omitted). In the present case, neither of the two prior art references cited in the Examiner's rejection, the Zujewski Abstract and Bishop, provide the public with a known or obvious way of making the compound recited in claim 16. The Examiner did not cite Bishop as teaching or suggesting the claimed compound. Rather, the Examiner cited Bishop only to show that, when treating breast cancer with the same category of compound as that recited in claim 16, a famesyl transferase inhibitor, the dosage regimen recited in claim 16 would have been obvious. See Final Act. 7. The Zujewski Abstract, the other prior art reference cited by the Examiner, discloses treating advanced cancer with a famesyl transferase inhibitor, like Bishop. See the Zujewski Abstract. Other than the therapeutic agent's biological activity as a famesyl transferase inhibitor, however, the Zujewski Abstract provides no structural details regarding the therapeutic agent, except for providing the arbitrary designation "Rl 15777." See id. Nor does the Zujewski Abstract include any detail as to how Rl 15777 may be prepared. See id. Indeed, it is undisputed that the Zujewski Abstract, even when viewed in combination with Bishop, does not provide any specific suggestion that Rl 15777 might be the compound recited in Appellants' claim 16. In other words, none of the prior art cited in the Examiner's rejection provides any disclosures that teach or suggest the specific compound recited in 2 Appeal2017-009075 Application 12/985,579 Appellants' claim 16, nor do the prior art references cited in the rejection explain how to make the compound of Appellants' claim 16. Nor, for that matter, do the prior art references cited in the Examiner's rejection teach or suggest treating cancer with the compound recited in claim 16. Rather, the prior art cited in the Examiner's rejection, at best, suggests treating cancer with Rl 15777, a therapeutic agent whose specific identity and method for preparation were not known to the public. Given these circumstances, the Examiner's rejection must be reversed, in my view. The Examiner, as well as my colleagues in the majority opinion set forth above, contend that the Zujewski Article remedies the deficiencies of the Zujewski Abstract and Bishop in relation to Appellants' claim 16. In particular, the Examiner cites the Zujewski Article as specifically identifying Rl 15777 as (+)-6-[amino(4- chlorophenyl)(l-methyl-lH-imidazol-5- yl)methyl]-4-(3-chlorophenyl)-l-methyl- 2(1H)-quinolinone, the compound of Appellants' claim 16. Ans. 8-9. Accordingly, the Examiner reasons, because Rl 15777 is inherently ( + )-6-[ amino( 4- chlorophenyl)(l-methyl- lH-imidazol-5-yl)methyl]-4-(3- chlorophenyl)- l-methyl- 2(1H)-quinolinone, and because the Zujewski Abstract describes treating advanced cancer with Rl 15777, "it was known" in the art to treat advanced cancer with (+)-6-[amino(4- chlorophenyl)(l- methyl-lH-imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl- 2(1H)- quinolinone. Ans. 8. In the present case, however, it is undisputed that the Zujewski Article is not prior art with respect to the rejected claims. See Appeal Br. 3. Thus, at best, the authors of the Zujewski Abstract might have known the chemical identity of Rl 15777, and how to make it. The prior art cited in the 3 Appeal2017-009075 Application 12/985,579 Examiners' rejection, nevertheless, does not establish that it was known by the public that Rl 15777 was (+)-6-[amino(4- chlorophenyl)(l-methyl-lH- imidazol-5-yl)methyl]-4-(3-chlorophenyl)-l-methyl- 2(1H)-quinolinone (the compound of Appellants' claim 16), nor did the public know how to make the compound. In that regard, as Appellants pointed out at oral argument (see Tr. 11 ), the present scenario is similar to the situation addressed by our reviewing court in Endo Pharmaceuticals Solutions, Inc. v. Custopharm Inc., 894 F .3d 1374 (Fed. Cir. 2018). I respectfully disagree with my colleagues' analysis, above, of Endo. Like here, Endo involved the issue of whether prior art publications ("the Articles") inherently described a composition recited in the claims at issue. See id. at 13 81-83. In Endo, like here, the Articles did not describe the specific makeup of the prior art composition, but it was later revealed that the formulation used in the Articles was the same as the composition recited in the claims at issue. Id. at 1381. In Endo, the court held that, because the Articles did not describe the composition in detail sufficient to allow a skilled artisan to determine the composition's identity or to prepare the composition, the Articles did not inherently describe the composition recited in the claims at issue. See id. at 13 83 ("Under the circumstances of this case, the incomplete description of the TU injection composition elements denied skilled artisans from having access to that composition, thereby precluding use of the inherency doctrine to fill in disclosure about the product missing from the Articles."). 4 Appeal2017-009075 Application 12/985,579 In the present case, as in Endo, the Examiner advances no evidence suggesting that the Zujewski Abstract, even when viewed in light of Bishop, described Rl 15777 in detail sufficient to allow skilled artisans to determine that Rl 15777 was the compound recited in Appellants' claim 16. Nor does the Examiner advance evidence suggesting that the prior art references cited in the rejection would have enabled skilled artisans to make either Rl 15777, or the compound recited in Appellants' claim 16. Accordingly, in my view, the Examiner's rejection should be reversed. In particular, as explained in Endo, the fact that the Zujewski Article later revealed Rl 15777 to be the compound recited in Appellants' claim 16 is insufficient to cure the absence of an enabling disclosure, in the prior art references cited in the rejection, of the claimed compound. See Endo, 894 F.3d. at 1381-83. My colleagues in the majority above cite to Appellants' Specification, which in tum cites to a prior art publication, WO 97/21701, as evidence that the level of skill in the art was such that skilled artisans would have known how to make the compound recited in Appellants' claim 16. WO 97/21701, however, is not one of the references cited by the Examiner in the rejection on appeal. Moreover, in my view, the majority's citation to Appellants' Specification is not for the proper purpose of determining the level of skill in the art, but instead is for the improper purpose of filling in gaps in the prior art references cited in the Examiner's rejection. See In re Morsa, 803 F.3d 1374, 1378 (Fed. Cir. 2015) ("There is a crucial difference between using the patent's specification for filling in gaps in the prior art, and using it to determine the knowledge of a person of ordinary skill in the art.") 5 Appeal2017-009075 Application 12/985,579 Lastly, I note the majority opinion's citation above of the American Association for Cancer Research ("AACR") policy, at the time the Zujewski Abstract was published, regarding the availability of materials described in articles submitted for publishing. It is unclear on this record, however, that the stated policy applies in the same fashion to abstracts published in the way the Zujewski Abstract appears in the journal, as opposed to articles actually submitted to the journal for publishing. See the Zujewski Abstract. The Examiner, moreover, did not cite the AACR policy as evidence to support the appealed rejection. In addition, neither the Examiner nor the majority opinion advances persuasive evidence showing that, even if the authors of the Zujewski Abstract had provided a sample of Rl 15777 to interested skilled artisans, the skilled artisans would have been able to determine how to make the compound. In sum, for the reasons discussed, the Examiner's rejection should be reversed, in my view. I, therefore, respectfully dissent from the decision in the majority opinion above to affirm the Examiner's rejection. 6 Md A Page j D,ib,:e L ,::, : ............................................................................... l ...................................................................................... ~ Application/Control No. Applicant(s)/Patent Under Reexamination Notice of References Cited Examiner Art Unit Page 1 of 1 U.S. PATENT DOCUMENTS * Document Number Date Country Code-Number-Kind Code MM-YYYY Name Classification 1 A US- 1 B US- C US- D US- E US- F US- G US- H US- I US- J US- K US- L US- M US- FOREIGN PATENT DOCUMENTS * Document Number Date Country Code-Number-Kind Code MM-YYYY Country Name Classification N 0 p Q R s T NON-PATENT DOCUMENTS * Include as applicable: Author, Title Date, Publisher, Edition or Volume, Pertinent Pages) u CANCER RESEARCH 1998 POLICY V w X *A copy of this reference is not being furnished with this Office action. (See MPEP § 707.05(a).) Dates in MM-YYYY format are publication dates. Classifications may be US or foreign. U.S. Patent and Trademark Office PT0-892 (Rev. 01-2001) Notice of References Cited Part of Paper No. 1 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC ~ -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 Updated 1/22/98 Cancer Research Instructions for Authors ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, UPDATES TO THESE "INSTRUCTIONS FOR AUTHORS" THROUGHOUT THE YEAR ARE HIGHLIGHTED IN FURFLE. ' ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~' Cancer Research, an official journal of the American Association for Cancer Research, Inc. (AACR), is devoted to the publication of significant, original studies in all areas of basic, clinical, translational and epidemiological cancer research. Topics include: biochemistry; biophysics; chemical, physical, and viral carcinogenesis and mutagenesis; clinical investigations including clinical trials; endocrinology; epidemiology and prevention; experimental pathology; experimental therapeutics; immunology and immunotherapy including biological therapy; molecular biology and genetics; physiology; radio biology and radiation oncology; tumor biology; and virology. Papers are stringently reviewed, and only those that report results of novel, timely, and significant research and meet high standards of scientific merit will be accepted for publication. CATEGORIES OF PUBLICATION The following types of material will be considered for publication: (1) Research articles that report original experimental, clinical, translational or epidemiological studies relating to cancer, which are well documented, novel, and significant. These articles are published within an average of 60 days from their acceptance. (2) Advances in Brief, which are short, definitive reports of highly significant and timely findings in the field. These submissions receive an accelerated review and, if acceptable, are published within an average of 10 weeks from receipt. Those deemed to be of the highest scientific merit and priority appear in print within 6-7 weeks of their receipt. Advances should be approximately 3 printed pages in length (about 12 double-spaced typescript pages), containing an Abstract of about 100 words, a one-paragraph Introduction, an abbreviated Materials and Methods section, Results and Discussion sections (which may be combined), a maximum of 20 references, and no more than 4 items for the display of data ( any combination of figures and tables). These guidelines will be strictly enforced. For any submission to this category that does not adhere to the guidelines, the Journal reserves the right to return the manuscript to the authors unreviewed. (3) Perspectives in Cancer Research, which are invited articles presenting fresh insights on either a very active or undeveloped area of research and viewpoints on where research in that area may or should be heading. (4) Reviews on subjects of timely interest and importance to cancer researchers. It is critical that these articles be written as concisely as possible in light of the limitations on space in the Journal. Authors of unsolicited reviews should submit an outline of the proposed article for approval by the Editorial Board. If submission of the complete article is encouraged, the review will be given particularly stringent editorial evaluation before acceptance. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 1/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 6 Letters to the Editor, o enng cons1 ere op1mons on manuscnpts pu 1s e m t e Journa . Correspon concerning articles that have not been published in Cancer Research will not be considered. (7) Brief meeting reports on symposia and conferences on cancer research. These reports should be submitted within 3-4 months of the meeting date in order to maintain their timeliness and should comprise no more than 3 printed pages (approximately 12 double-spaced typescript pages) and include a statement of the purpose(s) of the meeting, an integrated summary of the findings presented, and recommendations for future research. The names and affiliations of key speakers may be included if space is available. (8) Proceedings of symposia, published as external supplements to the Journal (Supplements to Cancer Research), the full expenses of which are assumed by the sponsoring agency. These proceedings are accepted for publication at the discretion of the Editor-in-Chief. Stringent acceptance criteria will be imposed. (9) Brief announcements of scientific meetings and of courses in cancer-related biomedical science of interest to our readers. These should be submitted at least 3 months prior to the expected month of issue. (10) Brief listings of recent deaths of distinguished contributors to the field of cancer research. EDITORIAL POLICIES Submission of a manuscript to Cancer Research implies that the author(s) of the paper understand and fully accept the policies of the Journal as detailed in these "Instructions for Authors." When a manuscript is submitted for consideration, the authors should confirm in writing that neither the submitted paper nor any similar paper, in whole or in part, other than an abstract or preliminary communication, has been or will be submitted to or published in any other primary scientific journal. Once an article is accepted for publication in Cancer Research, the information therein is embargoed from reporting by the print media until the journal's issue date and embargoed from reporting by all other media until 6 p.m. (EST) the evening before the issue date. It is also understood that all authors listed on a manuscript have agreed to its submission and content. For revised manuscripts, if an author is deleted or a new author is added, it is the responsibility of the corresponding author to provide the Publications Department with written documentation at the time of resubmission that the authors involved are aware of and agree to the changes in authorship. Cancer Research accepts no responsibility for such changes. The Journal maintains an international editorial board of Associate Editors with broad expertise in all areas of cancer research. These Associate Editors, along with a large group of external reviewers, provide fair and thorough evaluations of papers submitted to Cancer Research. When reviewing manuscripts, the Associate Editors and reviewers are expected to adhere to a strict code of ethical conduct in the review of scientific literature. This code mandates that the confidentiality of the material under review be maintained. Further details on appropriate conduct for Editors and reviewers can be found in Ethics and Policy in Scientific Publications (First Edition, 1992, published by the Council of Biology Editors, Inc., Northbrook, IL 60603). Journal policy requires that authors, reviewers, and Associate Editors reveal to the Editor-in-Chief any relationships that they believe could be construed as causing a conflict of interest with regard to the manuscript submitted for review. Submission of a manuscript implies acceptance by all authors of the strict policy of the Journal that under no circumstances will the identities or information leading to the identities of the Associate Editors and reviewers be revealed. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 2/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 SUBMISSION FEE AND PAGE CHARGES A nonrefundable submission fee of $75 is assessed for each manuscript and must be paid regardless of the decision rendered on the paper. Payment must be made at the time of submission either by check ( drawn on a U.S. bank) payable to the AACR, Inc., or credit card (Visa, Mastercard, or American Express). To pay by credit card, include the card number and expiration date in the covering letter accompanying your manuscript. Credit card payment is preferred for submissions from outside the U.S. Note: We will no longer accept purchase order payment for the manuscript submission fee. A page charge of $80 per printed page will be levied on all manuscripts accepted for publication. It is understood at the time of submission that the author( s) agree to pay this charge in the event of publication. Please refer to the section entitled "Publication Fees and Reprints" for further details regarding payment of this fee. Under exceptional circumstances, when no grant or other source of support exists, the author(s) may apply to the Editor-in-Chief at the time of submission for a waiver of the page charges. All such applications must be countersigned by an appropriate institutional official stating that no funds are available for the payment of page charges. PROCEDURES FOR SUBMISSION Contributions should be addressed to: Dr. Carlo M. Croce, Editor-in-Chief, Cancer Research, AACR, 150 S. Independence Mall West, Public Ledger Bldg., Suite 826, Philadelphia, PA 19106-3483; Phone: (215) 440-9300; FAX: (215) 440-9354. 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[]£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 Virology [The final category assignment of an article in an issue's Table of Contents is at the discretion of the Editors.] (10) five key words describing the paper, to assist in the selection of the Associate Editor and reviewers. Authors may suggest appropriate Associate Editors (the names of whom are listed in the front of each issue of Cancer Research) and reviewers to whom the manuscript could be assigned. Full addresses of suggested reviewers should be provided. Please note that final assignments are at the Editor-in-Chiefs discretion. Original submissions must include: (1) The author's covering letter in duplicate containing the above information. (2) Four copies of the manuscript and four sets of original illustrations. Indicate which set of original illustrations should be used by the printer in the event of publication. (3) Papers in press or submitted for publication which are highly relevant to the manuscript under review. Revised manuscript submissions must include: (1) A covering letter in duplicate, clearly indicating what alterations have been made in response to the criticisms raised. Satisfactory reasons should be given for noncompliance with any of the reviewers' recommendations for revision. (2) Four copies of the revised version of the manuscript, plus a red-marked copy of the manuscript indicating the changes made, and four sets of original illustrations. (3) A disk of the revised version of the manuscript to expedite typesetting the article in the event of publication. The disk must be accompanied by a completed Disk Submission Form, which can be found in the back of each issue of Cancer Research. (See "Typesetting from Disks" section later in these Instructions for further details.) 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Manuscripts that have been declined for publication will be reconsidered at the Editor-in-Chiefs discretion. An author of a rejected manuscript who wishes to resubmit must send a paper that has been revised in response to the criticisms, along with a covering letter in which the revisions are described. The manuscript identification number of the previous submission should be referenced in the covering letter. If the Editor-in-Chief determines that the paper can be reconsidered, it will be assigned a new manuscript identification number, the author will be charged a new manuscript submission fee, and the paper will undergo review as a new submission. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 4/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ \....;:".,. . •·' ~ .~~t\ ~- ~1 ;}~} " ~~ 1997 -~ ~}f:St; 1999 Papers should conform strictly to Journal style. A recent issue of Cancer Research will provide authors with assistance in the proper arrangement of papers. Manuscripts are to be written in clear, grammatical English. Papers that are not in Cancer Research style or that are not in good idiomatic English will be returned to the author without review. Laboratory jargon as well as terminology and abbreviations not consistent with internationally accepted guidelines should be avoided. t) ~'~ l~J For general and technical assistance in writing scientific papers, authors should refer to the following publications: Stedman's Medical Dictionary (Twenty-sixth Edition, 1995, The Williams & Wilkins Co., Baltimore, MD); CBE Style Manual (Sixth Edition, 1994, published by the Council of Biology Editors, Inc., Northbrook, IL); and The ACS Style Guide (First Edition, 1986, American Chemical Society, Washington, DC). Data must be presented concisely. Large masses of data of peripheral significance to the main thesis of the investigation will not be published in Cancer Research but may be deposited with the National Auxiliary Publications Service, c/o Microfiche Publications, P.O. Box 3513, Grand Central Station, New York, NY 10163- 3513; Phone: (516) 481-2300; FAX: (516) 481-6213. The manuscript should contain a footnote that indicates how this ancillary material can be obtained. Such data should be submitted for review along with the manuscript. The manuscript should be typed on 21.6- 28-cm (8- 11-inch) paper with double spacing throughout, allowing for ample margins. Manuscripts typed single-spaced or with typing on both sides of the page will be returned to the authors. Consecutive numbering of all pages is required, with the title page as page 1. The typescript should be arranged in the following order: (a) title, (b) author(s) and complete name(s) and location(s) of institution(s) or laboratory(ies), (c) running title, (d) key words, (e) footnotes, (j) text and references, (g) tables, (h) legends for all illustrations, (i) illustrations, and (j) other material. Numbered and lettered sections in the text should be avoided. The appropriate location for each table and illustration should be indicated by marginal notes. Simple chemical formulas or mathematical equations should be presented in a form that allows their reproduction in single horizontal lines of type; more complicated mathematical formulas or chemical structures difficult to set in type should be provided for reproduction in the form of line drawings or glossy photographs. Title. Titles should be brief but informative, and limited if possible to about 100 characters. It is important for literature retrieval to include in the title the key words necessary to identify the nature of the subject matter, including, if applicable, the species on which the work is done. Use of expressions such as "Studies on ... "or "Observations of ... " should be avoided, since they are not informative. Chemical formulas or abbreviations should not be used. Also, do not use Roman or Arabic numerals to designate that the paper is one in a series (see section below on Footnotes). Authors and Their Affiliations. 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Lengthy footnotes are discouraged since the same information can in most instances be presented more effectively in the text. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 5/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 should contain a definition for every nonstandard abbreviation used in the paper. For footnotes to tables, see section on Tables below. -~ ~}f:St; 1999 Abstract. The abstract, to appear at the beginning of the paper, should be concise, yet indicative of the content of the paper. In 1998, the abstracts of Cancer Research articles will be available on-line through the AACR Website (http://www.aacr.org). In light of this increased visibility and because abstracts are often copied directly by the secondary services, they should recapitulate in abbreviated form the purpose of the study and the experimental technique, results, and interpretations of the data. Data such as the number of test subjects and controls, strains of animals or viruses, drug dosages and routes of administration, tumor yields and latent periods, length of observation period, and magnitude of activity should be included. Vague, general statements such as "The significance of the results is discussed," or "Some physical properties were studied," are uninformative and not acceptable. All important terms relevant to the content of the paper should be incorporated into the abstract to assist indexers in the derivation of key words. Abbreviations should be kept to an absolute minimum; however, if they are needed, they must be properly identified so as to make the abstract independent of the text. Authors may wish to keep in mind that MED LINE, the computerized monthly bibliography prepared by the National Library of Medicine, includes only those abstracts that contain fewer than 6,000 bytes (or approximately 400 words). through that service. Introduction. It is not necessary to include all of the background literature in this section. Brief reference to the most pertinent papers generally suffices to acquaint the reader with the findings of others in the field and with the problem or question which the author's particular investigation addresses. Materials and Methods. Explanation of the experimental methods should be brief but adequate for repetition by qualified investigators. Procedures that have been published previously should not be described in detail but merely cited in appropriate references. Only new and significant modifications of previously published procedures need complete exposition. The sources of special chemicals or preparations used should be given along with their locations [city and state (country, if foreign)]. This Journal endorses the principles embodied in the Declaration of Helsinki and expects that all investigations involving humans will have been performed in accordance with these principles. In particular, papers reporting human experimentation must include a statement that the human investigations were performed after approval by a local Human Investigations Committee and in accordance with an assurance filed with and approved by the Department of Health and Human Services, where appropriate. Also, papers reporting biomedical research involving human subjects must include a statement that informed consent was obtained from each subject or subject's guardian. To obtain a copy of the Helsinki Declaration, please contact the World Medical Association, B6ite Postale 63, 01210, Perney-Voltaire Cedex, France. Further, the Journal is a staunch supporter of the most humane treatment of animals in the conduct of scientific studies. For animal experimentation reported in this Journal, it is expected that investigators will have observed the Interdisciplinary Principles and Guidelines for the Use of Animals in Research, Marketing and Education issued by the New York Academy of Sciences' Ad Hoc Committee on Animal Research, a copy of which is available for $5.00 from the Marketing Department, New York Academy of Sciences, 2 E. 63rd Street, New York, NY 10021-7289; Phone (212) 838-0230. Only results of those experiments, including photographic presentation of data, in which proper attention has been given to experimental ethical considerations toward animals will be published. Results. This section should include a concise textual description of the data presented in tables and illustrations. Excessive elaboration of data already given in tables and illustrations should be avoided. The Results and Discussion sections should be combined if, by so doing, space is saved or the logical sequence of the material is improved. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 6/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC ~ -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~1 ~'~ ;}~} ~~ l~J 1997 Before submission of the paper authors should verify the accuracy of all references and should check that all references have been cited in the text. Cancer Research style requires that all authors, complete titles of articles, and inclusive page numbers be supplied in the reference list. Examples of the two most common types of Journal references are: Saylors, R. L., III, Sidransky, D., Friedman, H. S., Bigner, S. H., Bigner, D. D., Vogelstein, B., and Brodeur, G. M. Infrequent p53 gene mutations in medulloblastomas. Cancer Res., 51: 4721-4723, 1991. Yuspa, S. H., Hennings, H., Roop, D., Strickland, J., and Greenhalgh, D. A. Genes and mechanisms involved in malignant conversion. In: C. C. Harris and L.A. Liotta (eds.), Genetic Mechanisms in Carcinogenesis and Tumor Progression, pp. 115-126. New York: Wiley-Liss, 1990. Journal articles and serial comP-endia. The complete title, journal, volume number, inclusive pages, and year of publication should be given. Serial compendia, such as Advances in Cancer Research and the Annual Review of Biochemistry, which appear annually in numbered sequence, should be cited as journals rather than books, thus omitting the names of publishers and editors. Serial Sources for the BIOSIS Previews Data Base (Volume 1997) should be consulted for abbreviations of journals and serials. Books and chaP-ter citations. Citation of a specific chapter or article in a book should carry the author(s) of the chapter, its title, editor(s) of the book, book title, edition, volume, inclusive pages of the chapter, location and name of the publisher, and year of publication. For references to complete books, give all of the above information that is pertinent. PaP-ers in P-ress. Papers in press may be listed among the references with the journal name and tentative year of publication. UnP-ublished material. Papers in preparation or submitted for publication, unpublished data, and personal communications should be cited in a footnote, not in the Reference section. The names of all authors should be given, along with manuscript titles if possible. Addenda. Data acquired after acceptance of the paper, by the authors themselves or by others, cannot be added to the text. An addendum may be included at the proof stage as a "Note Added in Proof," preceding the References section. However, such addenda are subject to approval by the Editor-in-Chief and could result in delay of publication. Addenda should be kept extremely brief. Tables. Tabular material should not duplicate data already presented in the charts. Unnecessary columns of data that can easily be derived from the rest of the results in the table should not be included. Large groups of individual values should be avoided; instead, these should be averaged and an appropriate designation of the dispersion such as standard deviation or standard error included. Authors are obliged to indicate the significance of their observations by appropriate statistical analysis. Every table must have a descriptive title and an explanatory paragraph that clearly gives the experimental details for understanding by the reader without reference to the text. Each column must carry an appropriate heading and, if numerical measurements are given, these units should be added to the column heading. Tables should be numbered with Arabic numerals and table footnotes should be indicated with superscript italic letters (a,b,c etc.). https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 7/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~1 ~'~ ;}~} ~~ l~J multiplied or divided to obtain the correct value. Illustrations. Both line drawings (graphs) and halftone illustrations (photographs, photomicrographs, electrophoretic patterns, etc.) should be designated figures. Figures should be used when salient points need illustration for better comprehension by the reader. Halftones are particularly expensive to reproduce and only those absolutely essential to the clarity of the presentation should be included. Straight-line functions such as relationships between concentration and absorbance, or Lineweaver-Burk plots when these are linear, should be described in a few lines in the text. Each figure should be labeled in pencil with the first author's name and the figure number on an adhesive label on the reverse side. For halftones, the top of the figure should also be noted. Legends are required for all figures. They should briefly describe the data shown; details in the text should not be repeated. Staining should be included for halftones, where applicable. Each legend should adequately identify all symbols, abbreviations, mathematical expressions, abscissas, ordinates, units, and reference points used on the figure. Line drawings, including flow diagrams and complex biochemical structures, should be prepared professionally (not simply typewritten). Illustrations should be provided on high-quality, smooth, opaque white paper or ordinary white bond paper. Tracing or textured papers are not acceptable. Illustrations should not be mounted on heavy cardboard. Clear, glossy prints are acceptable in lieu of original drawings, provided that all parts of the illustration are in focus. X-ray films or Polaroid photographs are not acceptable. If original drawings are submitted, they should not be larger than 21.6 28 cm (8 11 inches). Computer-generated graphs are acceptable provided that their quality adheres to the same standards as those produced by other means, e.g., all labeling must be clear and scaling must be in the proper proportion to reproduce legibly when reduced. Except for especially complicated drawings showing large amounts of data, all line drawn illustrations are published at one-column width (8.9 cm or 3 inches) or less. It is recommended that they be submitted in one- column size. If larger ones are submitted, it is the responsibility of the author to see that the abscissas, ordinates, lines, and especially the symbols are sufficiently large to permit reduction. When the graphs are reduced to the size of a single column, the letters and numbers must be at least 6 points and no larger than 12 points, and all symbols on the illustration must be discernible or the drawing will be returned to the author for correction. Do not use gray shading or screening in any graphs, particularly bar graphs. Gray does not reproduce well, especially if reduction is required. Use patterns consisting of solid black and white first. If further distinctions need to be made among elements on an illustration, use horizontal, vertical, diagonal, or cross-hatched lines. The thickness of ruled lines on graphs is also vital for clear presentation of the data. Avoid using fine, broken, or dotted lines. The symbols should be defined in the legend. Only those common symbols for which the printer has type should be used. Lines connecting the symbols should not extend beyond the data points. Graphs should be ruled off close to the area occupied by the curve, and abscissas and ordinates should be clearly marked with appropriate units. Explanations of the coordinates should not extend beyond the respective lines. Do not box-in graphs with top and right-hand frame lines unless these are essential for reference. Titles printed outside the confines of the drawing waste space; all of this information should be included in the legend. Also, to conserve space those curves that may appropriately appear together should be included in a single graph. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 8/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •'' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 divided) to give the correct value. Halftone illustrations should be submitted unmounted and trimmed to exclude all but essential material. The set of halftone illustrations intended for the printer's use must be made from original negatives, i.e., they must be first generation glossy prints. Photographs made from other prints are not acceptable for reproduction. Karyotypes should be presented in the form of cardboard plates onto which chromosome sections from an original photomicrograph are pasted. All halftones will be published at either 1(3")-, 1(5")-, or 2(7")-column width and placed as close as possible to their first citation in the text. Halftones must be prepared within these dimensions if they are to be reproduced without reduction; otherwise, they will be reduced to conform to these widths. Figure numbers should not be included on the face of the illustration. However, halftones that must appear together for comparison should be grouped under one figure number with each section lettered "A," "B," "C," etc., in the upper left-hand comer on the face of the illustration. Composite figures may be mounted on a plate, with the sections butted together and tooling (thin white lines) placed between the parts of the figure. For optimal reproduction, the contrast among photographs on a plate should be consistent. The overall dimensions of photographs on a plate should not exceed 18.4 22.4 cm (7 9 inches). The minimum dimensions to which the plate can be reduced must be indicated on the back. Symbols, arrows, or letters used in photomicrographs should contrast with the background. If pressure-sensitive labeling such as Chartpak, Letraset, or Prestype is used, tissue overlays should be placed on the halftone to prevent the lettering from chipping away. In general, tissue overlays are recommended to protect the surface of halftones. The important areas of the photographs that must be reproduced with greatest fidelity should be indicated on overlays. Internal scale markers should always be included on the photographs themselves as opposed to listing magnification in the legend since it may be necessary to reduce the figures. Magnifications given in the legend will reflect size before reduction. Color Photographs. Authors are encouraged to submit color illustrations. The expense of reproducing color photographs must be offset partially by the author. The cost of color reproduction charged to authors is $975 per color figure. If the illustration is a composite figure, the parts should be mounted together in as space-saving an arrangement as possible. All color illustrations must be submitted on flexible backing, including mounted composite figures. Please note that the author is responsible for submitting prints that are of sufficient quality to permit accurate reproduction, and for approving the final color proof. Cancer Research assumes no responsibility for the quality of the photograph as it appears in the Journal. Electronic Submission of Illustrations. Authors may submit illustrations on disk. Contact the AACR Publications Department for a form to enclose with illustrations submitted on disk. Color electronic images should be provided in Encapsulated PostScript (EPS) format. Black and white illustrations should be provided in Tagged Image File Format (TIFF) and sized to approximate column width. In all cases, original artwork should also be submitted with the disk. For more detailed information on submitting illustrations electronically, you can visit the Cadmus Website at btt1)://'t~js.cadxntts.corn./da~ or ~e11d f>,rnail to d1g1talaxt:\~f:c,r:H1rru1~_-corn, or can our I)1g1ta] /·trt i-Ielp L.1ne [tt 'l "~00"25'7-,5529, ext. 6985. ABBREVIATIONS Abbreviations are in general a hindrance to readers in fields other than that of the author(s), to abstractors, and to scientists in foreign countries. Authors should limit their use to an absolute minimum. Single words should not be abbreviated, e.g., daunomycin, folate, vincristine. Abbreviations are not to be used in titles, but running titles https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 9/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC section e ow on Terminology . A nonstan ar a reviatlons s footnote to the first such abbreviation after the Abstract. ~ -J.~\N APR .~~t\ ~-;}~} " -~ ~}f:St; 1999 Abbreviations that form recognizable words, such as EAT and MOPS, are discouraged. a) Standard Abbreviations. Authors may use, without definition, the abbreviations in the following lists. NAD+, NADH nicotinamide adenine dinucleotide and its reduced form NADP+, NADPH nicotinamide adenine dinucleotide phosphate and its reduced form (DPN+, TPN+, and their reduced forms are not acceptable.) CoA, acyl-CoA coenzyme A and its acylderivatives (e.g., acetyl) AMP, GMP, IMP, the 5-phosphates ofribosyladenine, -guanine, -inosine, -uracil, UMP, CMP, TMP -cytosine, and-thymine ADP, etc. the 5(pyro )-diphosphates of adenosine, etc. ATP, etc. the 5(pyro )-triphosphates of adenosine, etc. dAMP, dGMP, dIMP the 5-phosphates of 2-deoxyribosyl-adenine, etc. RNA, DNA ribonucleic acid, deoxyribonucleic acid RNase, DNase ribonuclease, deoxyribonuclease cDNA complementary DNA mRNA messenger RNA nRNA nuclear RNA rRNA ribosomal RNA tRNA transfer RNA (sRNA is not recommended for RNA preparations that accept amino acids.) Pi, PPi orthophosphate, pyrophosphate Tris tris(hydroxymethyl)methylamine EDTA ethylenediaminetetraacetate PO POP 1,4-bis[2-(5-phenyloxazolyl) ]benzene PPO 2,5-diphenyloxazole DEAE, TEAE diethylaminoethyl, triethylaminoethyl UV, IR ultraviolet, infrared https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm ,--;:s\ \....;:".,. . •·' t) ~1 ~~ ~'~ l~J 10/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC mo ar mo es 1 er m no use or mo es millimolar mm (preferred to 103 m) ( millimo les/li ter) micromolar m (preferred to 106 m) (micromoles/liter) nanomolar nm (not mm) picomolar pm (not m) ~ -J.~\N .~~t\ ;}~} -~ ~}f:St; APR a) ,--;:s\ t) \....;:".,. . •·' ~- " ~1 ~~ ~'~ l~J 1999 The expression mg % should be avoided; weight concentrations should be given as g per ml, g per 100 ml, g per liter, etc. Units of Length, Area, Volume, Mass, Time The abbreviations below are correct for both singular and plural forms of each term. meterm centimeter cm square centimeter cm2 millimeter mm micrometer (not micron) m (not) nanometer (not millimicron) nm (not m) picometer (not micromicron) pm (not) Angstrom (0.1 nm) A liter not abbreviated milliliter ml microliter 1 (not ) gramg milligram mg microgram g (not) kilogram kg hourh https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 11/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC nzts retardation factor Rf acceleration of gravity g sedimentation coefficient s sedimentation coefficient in s20,w water at 20 degree Celsius (Centrigrade) C degree Fahrenheit F KelvinK diffusion coefficient D equilibrium constant K inhibition constant Ki Michaelis constant Km maximum velocity Vmax Others molemol Curie Ci equivalent eq counts per minute cpm disintegrations per minute dpm revolutions per minute rpm voltV Svedberg unit S absorbance A (not O.D.) probability P roentgen R standard deviation SD https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm ~ 1997 -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J -~ ~}f:St; 1999 12/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC n entropy S molecular weight Mr base pair bp kilobase kb In chemical compounds ortho o metam parap secondary sec tertiary tert Routes of administration intramuscular i.m. intraperitoneal i.p. intravenous i. v. oral p.o. subcutaneous s.c. ~ 1997 TERMINOLOGY -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J -~ ~}f:St; 1999 Approved terms and abbreviations for chemical substances have been collected in the Compendium of Biochemical Nomenclature and Related Documents, International Union of Biochemistry, Second Edition, 1992. This volume is available from: Portland Press Inc., Ashgate Publishing Co., Old Post Road, Brookfield, VT 05036; Phone: (802) 276-3162; FAX: (802) 276-3837. Included are all recommendations issued by the IUPAC- IUB Commission on Biochemical Nomenclature in the following areas: general abbreviations and symbols; abbreviations and symbols for chemical names of special interest in biological chemistry; stereochemistry; natural products and related compounds; isotopically labeled and modified compounds; biochemical equilibrium data; alpha-amino acids; symbols for aminoacid derivatives and peptides; synthetic modifications of natural peptides; synthetic polypeptides or polymerized amino acids; aminoacid sequences; conformation of polypeptide chains; peptide hormones; human immunoglobulins, multiple forms of enzymes; nucleic acids, polynucleotides, and their constituents; lipids; steroids, quinones with isoprenoid side chains; carotenoids; tocopherols and related compounds; carbohydrates; cyclitols; phosphorus-containing compounds of importance in biochemistry; folic acids and related compounds; vitamins B6 and related compounds; corrinoids. Isotopically Labeled Compounds. A radioactive nuclide is indicated by its mass number as a superscript to the left of the symbol (32P); when written out, it should correspond to the spoken word (phosphorus-32). https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 13/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~1 ~'~ ;}~} ~~ l~J element, as in [ 14C2]glycolic acid. The symbol U indicates uniform labeling and G, general labeling, e.g., [U- 14C]glucose (where the 14c is uniformly distributed among all six positions) and [G-14C]glucose (where the 14c is distributed among all six positions, but not necessarily uniformly). The isotopic prefix precedes that part of the name to which it refers, as in sodium [1 4C]formate, iodo[14C2]acetic acid, I-amino[ 14C]methyl-cyclopentanol, B-naphth[ 14C]oic acid, 2-acetamido-7-[ 131 I]iodofluorene, fructose 1,6-[I-32P]bisphosphate, 17alpha-[3H]estradiol. Terms such as "131I-labeled albumin" should not be contracted to 11 [1 31I]albumin" (since native albumin does not contain iodine), and "14C-labeled amino acids" should similarly not be written as "[14C]amino acids" (since there is no carbon in the amino group). When isotopes of more than one element are introduced, their symbols should be arranged in alphabetical order, e.g., [3-14c; 2,3-D; 15N]serine. Deuterium and tritium may be designated as 2H and 3H or as D and T, respectively. When not sufficiently distinguished by the foregoing means, the positions of isotopic labeling are indicated by Arabic numerals, Greek letters, or prefixes in italics, as appropriate; these are to be placed within square brackets to appear before the symbol of the element concerned and are attached to it by a hyphen. Examples of this style are [I-14C]alanine, l-[2-14C]leucine or l-[- 14C]leucine, [carboxy-14C]leucine, [2,3-14C]maleic anhydride, [3,4-14C, 35S]methionine, l-[methyl-14C]methionine. The symbol indicating configuration always precedes the bracketed isotope, and a hyphen is used to separate it from the brackets, e.g., d-[1 4C]-glucose; l-[l- 14C]leucine. The same rules apply when the labeled compound is designated by a standard abbreviation or symbol other than the atomic symbol, e.g., [-32P]ATP, [32P]CMP, or [1 25I]IdUrd. The square brackets are not to be used, however, with atomic symbols, or when the isotopic symbol is attached to a word that is not a specific chemical name, abbreviation, or symbol. Proper usage here is: 14C02, 2H20, H235S04, 32pi, 131I-labeled, 3H-ligands, 14C- steroids. Enzymes. Authors should use the Recommended Name given in Enzyme Nomenclature 1992: Recommendations of the Nomenclature Committee of the International Union of Biochemistry on the Nomenclature and Classification of Enzymes (Academic Press, Inc., Orlando, FL, 1992). In some cases the Systematic Name or the reaction catalyzed should also be included. It is strongly recommended that the Enzyme Commission number be stated at first mention. For information on isozyme nomenclature, consult Biochemical Nomenclature and Related Documents, mentioned previously. Histones. The six histone fractions are to be labeled HI, HI 0 , H2A, H2B, H3, and H4, rather than Fl, Fl 0 , F2a2, F2b, F3, and F2al, respectively. Interferon Assays. When reporting the calibration of interferon assays, authors should state the name, identifying number, and assigned potency of the international standard used to calibrate their assay, along with the observed geometric mean titer of the standard, the standard deviation of that value, the number of titrations performed to obtain that value, and the technical details of the assay. Inbred Strains. Designations for inbred mouse strains should conform to the guidelines in "Standardized Nomenclature for Inbred Strains of Mice: Eighth Listing," Cancer Res., 45: 945-977, 1985, prepared by Joan https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 14/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' ~ .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 Outbred Animal Stocks. Nomenc ature or out re a oratory amma s s ou con orm to t at recommen e y the Committee on Nomenclature, Institute of Laboratory Animal Resources: "A Nomenclature System for OutbredAnimals," Lab. Animal Care, 20: 903-906, 1970. Drugs. Generic names of drugs are preferred; a proprietary name may be used only after the first mention of the generic name and should be avoided in titles unless both names can be listed easily. If a foreign proprietary name is used, the name of the comparable U.S. product should be given. When there is no generic name for a drug, authors should give the chemical name or formula or a description of the active ingredients. Authors should refer to the formally adopted generic names listed in USAN and the USP Dictionary of Drug Names (1998). Tumors. Tumors used in experimental investigations should be clearly described and identified in acceptable terminology. If these tumors are well known and have been identified in previous publications, extended descriptions and photomicrographs are unnecessary. Authors of clinical papers are encouraged to use the TNM staging system approved by the International Union Against Cancer and the American Joint Committee on Cancer, whenever applicable. General. The composition of all solutions and buffers should be specified in sufficient detail so that the concentration of each component can be determined. The word "saline" should be replaced by "NaCl solution," along with the exact concentration. Inexact terms such as "physiological saline" or "phosphate-buffered saline" are not permitted; exact contents and concentrations should be given. Decimals are preferred to fractions; the form 0.01, not .01, is required in text, tables, and illustrations. Ionic charge should be designated by a superscript immediately following the chemical symbol, e.g., Mg2+, s-. POLICY CONCERNING AVAILABILITY OF MATERIALS It is understood that by publishing any work in Cancer Research the authors agree to make freely available to other academic researchers any of the cells, clones of cells or DNA or antibodies, etc. that were used in the research reported and that are not available from commercial suppliers. Also, authors may be required to make primary data available to the Editor-in-Chief in cases of dispute. TYPESETTING FROM DISKS To expedite publication, Cancer Research is now copy editing accepted manuscripts electronically. When submitting revised manuscripts, authors are encouraged to send a disk of the paper along with the required four hard copy printouts. If the manuscript is accepted, the disk, with the printout as backup, will be sent to our printer, where the article will then be copy edited on-line and typeset from the disk. The disk should contain all the parts of the manuscript on one file. However, tables and mathematical material, such as equations, may be excluded from the disk file because they must still be copy edited and typeset in the traditional manner from the accompanying hard copy. The disk will ultimately be returned to the authors. Please label the outside of the disk with Cancer Research, the first author's name, a partial title of the manuscript, and the name of the computer file used to access the manuscript on disk. In addition, we will need to know the name of the computer used (e.g., IBM/PS2), the name of the operating system and version (e.g., DOS 3.3), and the word processing program and version (e.g., WordPerfect 5.0). Please provide this information to https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 15/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC ~ -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 compatl e computers are pre erre , ut t ose pro uce on some App e or Wang computers can a so e converted. The following word processing programs can be converted, XyWrite III Plus, XyWrite for Windows, Word Perfect (IBM or Macintosh), Word Perfect for Windows, Microsoft Word (IBM or Macintosh), Word for Windows, WordStar, Microsoft Works, Ami Pro, Mac Write, Mac Write II, Mac Write Pro, Display Write, MultiMate, Volkswriter, Enable, Lotus Manuscript, Mass 11, Professional Write, Total Word, Write Now, FullWrite, Wang OIS (WPS), CPT 8000, and TEX formatted files. Authors preparing diskettes on Macintosh computers should not use the Fast Save option. Files in ASCII can also be used, but are not preferred. However, even if your program is not in the preceding list, send in your disk with an appropriately completed Disk Submission Form and we will attempt to typeset from it. New releases of word processing software are not always immediately available for conversion. In addition, because of the file structures and internal coding, we cannot accept disks created on desktop publishing systems or those created on proprietary typesetting systems. We also cannot guarantee that all special characters (such as Greek letters and symbols used in mathematical expressions) can be translated. We ask that authors check their proofs carefully to ensure that all special characters converted properly. The Journal does not assume responsibility for errors in the conversion of newly released software, customized software, or special characters. Note: It is imperative that the authors ensure that the disk file is the most recent version of the manuscript and that it matches the most recently submitted hard copy. ALTERATIONS IN PROOF The Journal provides authors with page proofs for their examination. We urge our contributors to proofread and edit their manuscripts carefully before submission because alterations in proof are costly and, if extensive, can lead to publication delays. Authors will be charged for excessive changes in proof not due to printer's errors. The Editors retain the prerogative to question minor stylistic alterations and major alterations that might affect the scientific content of the paper. Page proofs should be returned to the AA CR Publications Department within 2 4 hours of receipt via an overnight delivery service. Proofs not received by the deadline will be published without the authors' corrections. Authors who will not be available to read their proofs should appoint someone to handle the proofreading of their articles in their absence. PUBLICATION FEES AND REPRINTS Publication fees for Cancer Research articles include a charge of $80/printed page levied on all but invited articles and a color reproduction cost of $975/color figure for articles with color. These fees are itemized on the reprint order form that is sent to authors along with their proofs. If this form is not in your proof package, the AACR Publications Department should be contacted immediately [Phone: (215) 440-9300; FAX: (215) 440- 9354]. The reprint order form must be completed and returned 2 weeks before publication, even if reprints are not desired, because payment information for the publication fees is required. Failure to return the form with this information will delay publication of your article. Prepayment for publication fees and, if desired, for reprints, can be made in the form of a check (in U.S. dollars, drawn on a U.S. bank), signed institutional purchase order, or credit card (VISA, Mastercard, American Express) information supplied on the reprint order form, which serves as a proforma invoice. Return the order form and payment made payable to: American Association for Cancer Research, P.O. Box 631060, Baltimore, MD 21263- 1060. https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 16/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC -J.~\N APR ~ .~~t\ ~-;}~} " 1997 -~ ~}f:St; 1999 mqumes regar mg repnnts, p ease contact Ca mus Journa Services Repnnt Department [P 9190 or (410) 819-3992; FAX: (410) 820-9765]. a) ,--;:s\ \....;:".,. . •·' t) ~1 ~~ ~'~ l~J Finally, it is helpful to the reader if a footnote is included in the paper indicating to which author reprint requests should be addressed. COPYRIGHT AND PERMISSIONS Under the copyright law (PL 94-553) which became effective January 1, 1978, copyright for written material is vested in the author from the moment of its creation and remains the property of the author until legally transferred. For this reason it is necessary to require that all authors who wish to publish in Cancer Research formally transfer copyright to the proprietor of the Journal, namely, the AACR. It is understood by this transfer that the authors relinquish all exclusive rights of copyright ownership, including without limitation all rights of reproduction, derivation, distribution, sale, and display of the work, in whole or in part, in any and all forms of media now or hereafter known. However, the Journal will routinely allow authors ( or others with the permission of the authors) to include select parts of a copyrighted article in reviews, books, or subsequent papers, upon written request to the AACR Publications Department. Requests to reproduce an article in its entirety will be considered on an individual basis and permission may be granted contingent upon payment of an appropriate copyright fee. All reproduction requests must include a brief description of intended use and a stamped, self- addressed envelope. Third parties should obtain the approval of the authors before corresponding with the AACR Publications Department. It is understood in conveying copyright that the authors have not published this material elsewhere, either whole or in part ( except in abbreviated form as a preliminary communication), and that they have neither concluded previous negotiations nor initiated pending negotiations for copyright of this material. When a manuscript has been written by two or more authors, one of them should be designated senior author who will negotiate copyright transfer in the name of all of the authors. The duly authorized agent of a commercial firm or commissioning organization must sign our copyright transfer form if the author prepared the article as part of his or her official duties as an employee. The federal government has determined that it has a nonexclusive right to publish or republish material developed from work performed under federal grant-supported projects. Therefore, copyrights for such works are subject to this restriction. Since the federal government does not recognize private copyright for work performed by its employees as part of their official duties, the Journal will accept papers from government laboratories without copyright transfer, provided that the authors abide by the same provisions required of other authors and sign the appropriate section of our copyright transfer form. Appropriate forms for transfer of copyright will be sent routinely with acknowledgment of receipt of manuscripts. They may also be requested from the AACR Publications Department. The Journal will not publish a paper unless the form is properly filled out and signed. Articles the work and publication of which are subsidized totally by the federal government are understood to be in the public domain and may be copied without restriction or payment of a fee. Copies of the remaining articles in Cancer Research may be made for personal or internal use, provided that the copier pay a per-copy fee of $4.00 through the Copyright Clearance Center, Inc. This Center is a nonprofit organization through which individuals and institutions may reimburse a copyright owner for photocopying of journal articles beyond what is defined as "fair use" in Sections 107 and 108 of the Copyright Revision Act of 1978. The appearance of a fee https://web.archive.org/web/19980130101733/http://www.aacr.org/caninst.htm 17/18 5/1/2019 Cancer Research thttp ://www.aacr.org/ca n inst. htm ---------------------------------------------------------------------------------------------------! []£] DEC ~ -J.~\N APR a) ,--;:s\ t) \....;:".,. . •·' .~~t\ ~- ~1 ~'~ ;}~} " ~~ l~J 1997 -~ ~}f:St; 1999 Those who wish to photocopy articles for which the AACR holds the copyright should report the title of the Journal, the month and year of publication, the initial page number of the article, the number of copies made, and the appropriate fee code to: Copyright Clearance Center, Inc., 222 Rosewood Drive, Danvers, MA 01923; (508) 750-8400. Remittances may be sent to the Center at the time of reporting or the Center will bill the user on a monthly basis. Deposit accounts and prepayment plans may also be arranged. ADVERTISEMENTS Advertisement insertion orders and copy must be received approximately 5 weeks prior to the date of the issue in which the advertisement is to be published. The Journal is mailed approximately 5 days before the date of issue; issues are dated the 1st and the 15th of each month. Inquiries regarding advertising should be directed to: M.J. Mrvica Associates, Inc., 2 West Taunton Ave., Berlin, NJ 08009; Phone: (609) 768-9360; FAX: (609) 753- 0064. SUBSCRIPTIONS AND BUSINESS INQUIRIES Cancer Research is published twice a month, one volume per year, by the AACR. Subscriptions include the Proceedings of the American Association for Cancer Research, issued in March of each year. Except for members of the Association, all subscriptions are payable in advance to AACR, Subscription Office, P.O. Box 11806, Birmingham, AL 35202 [Telephone: (800) 633-4931 or (205) 995-1567; FAX: (205) 995-1588], to which all business communications, remittances (in United States currency or its equivalent), and subscription orders should be sent. In Japan, send orders and inquiries to (sole agent): USACO Corporation, Tsutsumi Bldg., 13-12, Shimbashi 1-chome, Minato-ku, Tokyo 105, Japan; Phone: (03)502-6471. The regular annual subscription price of Cancer Research for members of the AACR is $90. Individuals who are not AACR members may subscribe to Volume 58 (1998) of Cancer Research at the rate $495 U.S./$585 foreign. Cancer Research is only available to institutions as a combined subscription with Clinical Cancer Research. The combined 1998 institutional subscription price of $795 U.S./$925 foreign includes a subscription to Clinical Cancer Research. Canadian subscribers should add 7% GST. Changes of address should be sent 60 days in advance and include both old and new addresses. Member subscribers should send changes of address to: AACR Member Services, 150 S. Independence Mall West, Public Ledger Bldg., Suite 826, Philadelphia, PA 19106-3483. Nonmember subscribers should send changes of address to: AACR Subscription Office, P.O. Box 11806, Birmingham, AL 35202. No responsibility is accepted by the Editors, by the AACR, Inc., or by Cadmus Journal Services for opinions expressed by the contributors or for the content of advertisements. 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