Ex Parte Garcia et alDownload PDFPatent Trial and Appeal BoardFeb 27, 201713786323 (P.T.A.B. Feb. 27, 2017) Copy Citation United States Patent and Trademark Office 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 APPLICATION NO. FILING DATE FIRST NAMED INVENTOR ATTORNEY DOCKET NO. CONFIRMATION NO. 13/786,323 03/05/2013 Louie Daniel Garcia PCIRA.029D1 9436 20995 7590 03/01/2017 KNOBBE MARTENS OLSON & BEAR LLP 2040 MAIN STREET FOURTEENTH FLOOR IRVINE, CA 92614 EXAMINER KISHORE, GOLLAMUDI S ART UNIT PAPER NUMBER 1612 NOTIFICATION DATE DELIVERY MODE 03/01/2017 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): jayna.cartee@knobbe.com efiling @ knobbe. com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte LOUIE DANIEL GARCIA, LOIS GIBSON, WILLIAM JOSEPH LAMBERT, BENJAMIN W. LI, and LIANG JIN ZHU Appeal 2016-0069171 Application 13/786,323 Technology Center 1600 Before DONALD E. ADAMS, RICHARD J. SMITH, and DAVID COTTA, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL2 This appeal under 35 U.S.C. § 134(a) involves claims 1, 3-15, 22, 23, and 76-84 (Non-Final Act. I).3 Examiner entered rejections under 35 U.S.C. § 103(a) and obviousness-type double patenting. We have jurisdiction under 35 U.S.C. § 6(b). We AFFIRM-IN-PART. 1 This Appeal is related to Appeal 2016-006897, Application 12/914,944 (Br. 3). 2 Appellants identify the real party in interest as “PACIRA PHARMACEUTICALS, INC.” (Br. 3). 3 Examiner’s March 19, 2015 Non-Final Office Action. Appeal 2016-006917 Application 13/786,323 STATEMENT OF THE CASE Appellants’ disclosure “relates to multivesicular liposome (MVL) formulations of methotrexate (MTX) which minimize the side effects of MTX while maintaining or improving efficacy” (Spec. ^ 2). Claim 1 is representative and reproduced below: 1. A formulation comprising multivesicular liposomes for administration by injection, said multi vesicular liposomes comprise an amount of a basic addition salt of methotrexate, one or more amphipathic lipids or salts thereof, one or more neutral lipids, and optionally cholesterol or plant sterols, wherein the formulation is substantially cyclodextrin free, wherein administration of a single dose of said formulation to a subject in need thereof results in a plasma Cmax of said methotrexate of from 5% to 50% of the plasma Cmax of immediate release dosage forms of methotrexate, and wherein a duration of said methotrexate in the subject is from about 1 to about 30 days. (Br. 19 (emphasis added).) Claims 3-15, 22, 23, and 76-84 depend directly or indirectly from Appellants’ claim 1 (see Br. 19-20). The claims stand rejected as follows: Claims 1, 3-5, 7-15, 22, 23, and 76-84 stand rejected under 35 U.S.C. § 103(a) as unpatentable over Hartounian,4 Kim ’147,5 and Kim ’5736 alone or in combination. Claims 1, 3-15, 22, 23, and 76-84 stand rejected under 35 U.S.C. § 103(a) as unpatentable over Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Heath.7 4 Hartounian et al., WO 99/25319 Al, published May 27, 1999. 5 Kim et al., US 5,723,147, issued Mar. 3, 1998. 6 Kim, US 5,759,573, issued June 2, 1998. 7 Heath et al., US 4,565,696, issued Jan. 21, 1986. 2 Appeal 2016-006917 Application 13/786,323 Claim 7 stands rejected under 35 U.S.C. § 103(a) as unpatentable over Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Walsh,8 Hendrix,9 Low,10 and Shirley.* 11 Claim 7 stands rejected under 35 U.S.C. § 103(a) as unpatentable over Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Heath, Walsh, Hendrix, Low, and Shirley. Claims 1, 3-5, 7-15, 22, 23, and 76-84 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 59-78 of copending Application 13/786,368. Provisional Obviousness-type Double Patenting'. Appellants do not contest the provisional rejections (see Br. 4). Therefore, the rejection is summarily affirmed and will not be further discussed. See MANUAL OF PATENT EXAMINING PROCEDURE § 1205.02 (“If a ground of rejection stated by the examiner is not addressed in the appellant's brief, that ground of rejection will be summarily sustained by the Board.”). Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? 8 Walsh, US 2007/0093497 Al, published Apr. 26, 2007. 9 Hendrix, US 2006/0116334 Al, published June 1, 2006. 10 Low et al., US 2002/0192157 Al, published Dec. 19, 2002. 11 Shirley et al., US 6,306,432 Bl, issued Oct. 23, 2001. 3 Appeal 2016-006917 Application 13/786,323 FACTUAL FINDINGS (FF) FF 1. Hartounian “relates to emulsification processes for preparing multivesicular liposome [(MVL)] formulations, with sustained release characteristics and the formulations produced by those processes” (Hartounian 1:9-11; see generally Ans. 3). FF 2. Hartounian “provides a process for producing MVL by providing a water in oil (w/o) emulsion, which is made from an aqueous phase dispersed in a solvent phase containing amphipathic and neutral lipids” (Hartounian 4: 24-26). FF 3. Hartounian discloses that “[i]n general, for making multivesicular liposomes, it is required that at least one amphipathic lipid and at least one neutral lipid be included in the lipid component,” wherein [t]he neutral lipid component can comprise a single neutral lipid, or the neutral lipid component can comprise a mixture of a slow release neutral lipid and a fast release neutral lipid in a molar ratio range from about 1:1 to 1:100 . . . , wherein the rate of release of the biologically active compound decreases in proportion with the increase in the ratio of the slow release neutral lipid to the fast release neutral lipid. (Hartounian 14: 10-11; id. at 14: 28 - 15: 3; see also id. at 11: 3-12 (Hartounian discloses a process for producing MVLs, wherein “an acid or other excipient [is used] for modulating the release rate of the encapsulated biologically active substances from the MVL”)). FF 4. Hartounian discloses methotrexate (MTX) as a physiologically active substance that may be included within the MVL, wherein “[a]ny pharmaceutically acceptable salt of a particular physiologically active substance which is capable of forming such a salt is also envisioned as being useful in the present invention, including halide salts, phosphate salts, 4 Appeal 2016-006917 Application 13/786,323 acetate salts, and other salts” (Hartounian 16: 13-15 and 25 (emphasis added); see generally Ans. 3 and 4; cf. Br. 4 (Appellants’ claim 4 (“The formulation as in Claim 1, wherein the basic addition salt of methotrexate is a potassium salt”)). FF 5. Hartounian discloses that the MVL formulation may be administered by injection (see Hartounian 17: 4-6; id. at 31: 10-13; see generally Ans. 7). FF 6. Hartounian discloses a general method for preparing MVLs that comprises combining first and second emulsions, wherein the second emulsion “can comprise pH buffering agents, osmotic agents, sugars, amino acids, electrolytes, preservatives, and other excipients known in the art of semi-solid dosage forms. Examples of such constituents include lysine, dextrose, and glucose” (see Hartounian 20: 21-24; see generally id. at 13- 31). FF 7. Hartounian exemplifies the preparation of a number of MVLs containing various physiologically active substances in the presence of an acid or a base (see generally Hartounian 34: 12-19 (exemplifying “an aqueous solution including[, inter alia,] morphine sulfate [and] 10% hydrochloric acid”)); id. at 40: 5-25 (exemplifying “[a] cytarabine preparation [comprising] HC1 (10% w/v);” “[a] morphine preparation [comprising] HC1 (10% w/v),” and “[a]n insulin-like growth factor (IgF-1) preparation [comprising] 0.041 NNH4OH”)). FF 8. Kim ’147 “relates to the composition of synthetic [MVLs] or liposomes encapsulating biologically active substances and to method for their manufacture and use” (Kim ’147 1: 18-21; see generally Ans. 3). FF 9. Kim ’147 discloses that “the addition of a hydrochloride, such as hydrochloric acid or other hydrochlorides such as lysine hydrochloride, is 5 Appeal 2016-006917 Application 13/786,323 essential for high encapsulation efficiency and controlled release rate of encapsulated molecules in biological fluids and in vivo” (Kim ’ 147 3:51- 56). FF 10. Kim ’573 discloses “[ljiposomes containing cyclodextrin in the encapsulated aqueous phase are useful for encapsulation of biologically active substances, especially those which are hydrophilic” (Kim ’573, Abstract; id. at 4: 14-34 (Kim ’573 “is directed to forming inclusion complexes of water-soluble compounds, such as methotrexate, with cyclodextrins, preferably [3-cyclodextrin, and to encapsulating the inclusion complex into liposomes for controlled release,” wherein the “formation of an inclusion complex results in a reduction in the rate of release of the hydrophilic compound from the liposome compared to the rate of release of the same compound encapsulated in the absence of the cyclodextrin”). FF 11. Kim ’573 exemplifies the synthesis of liposomes “encapsulating methotrexate in the presence of cyclodextrin,” wherein the synthesis comprises the preparation of a “discontinuous aqueous phase[, which] consisted of 2-hydroxypropyl-[3-cyclodextrin solution (100 mg/ml), HC1 (0.1N) and methotrexate (10 mg/ml)” (Kim ’573 7: 56-62; see generally Ans. 3). FF 12. Los declares, inter alia, that Hartounian and Kim ’147 disclose processes for the preparation of MVLs or liposomes that comprise the addition of an acid (see Los Dec.12 ^ 4). FF 13. Los declares that “a basic [addition] salt of methotrexate, for example, sodium methotrexate or potassium methotrexate [] cannot exist in an acidic environment” (Los Dec. ^ 6). 12 Declaration of Kathleen Los, signed Sept. 18, 2014. 6 Appeal 2016-006917 Application 13/786,323 FF 14. Examiner finds that Hartounian, Kim ’147, and Kim ’573 “do not teach the use of methotrexate sodium or potassium salts” and relies on Heath to make up for this deficiency in Hartounian, Kim ’ 147, and Kim ’573 taken alone or in combination (Ans. 4). FF 15. Heath exemplifies the “Preparation of Methotrexate Encaptured BSA-vesicle Conjugates,” wherein “[t]he liposomes were prepared in a solution which contained 50 mM methotrexate (sodium salt), 50 mM morpholinoethanesulphonic acid, 50 mM morpholinopropanesulphonic acid, pH 6.7” (Heath 5: 3-11; see generally Ans. 4 and 8-9). FF 16. Examiner finds that Hartounian, Kim ’147, and Kim ’573 taken alone or in combination with or without Heath fails to suggest a composition that “inclu[des] [] folate,” and relies on Walsh, Hendrix, Shirley, and Low to make up for this deficiency in Hartounian, Kim ’ 147, and Kim ’573 taken alone or in combination with or without Heath (Ans. 5). ANALYSIS Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with or without Heath'. Based on Hartounian, Kim ’ 147, and Kim ’573 alone or in combination, taken with or without Heath, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious to have an MLV comprising a basic addition salt of MTX that exhibited a release profile that is “the same as” is required by Appellants’ claimed invention (Ans. 3). In this regard, Examiner finds that a person of ordinary skill in this art would have used routine optimization to adjust the release profile of the MVL to obtain any desired release rate (Ans. 3—4; see also id. at 7). Examiner further asserts that “[t]he criticality of the use of an additional salt of methotrexate is not readily apparent to the examiner 7 Appeal 2016-006917 Application 13/786,323 [because] methotrexate [was] known to exist in a salt form such as a sodium salt and [Hartounian discloses] either the active agents or their salts could be used in the formulation of MVL comprising active agents” (Ans. 4). We are not persuaded. Appellants’ claimed formulation requires, inter alia, MVLs that comprise an amount of a basic addition salt of methotrexate {see Br. 19 (Appellants’ claim 1). Thus, notwithstanding Examiner’s contention to the contrary, the criticality of the basic addition salt of methotrexate is clear from Appellants’ claimed invention, which requires, inter alia, that the MVLs comprise a basic addition salt of methotrexate {see Br. 19 (Appellants’ claim 1); cf Ans. 4). Hartounian’s generic disclosure of the preparation of MVLs suggests a process for formulating MVLs, wherein “an acid or other excipient for modulating the release rate of the encapsulated biologically active substances from the MVL” is used and that the ratio of slow and fast release neutral lipids present in the MVL may be modified to adjust the MVL’s release rate (LL 3). Hartounian, however, exemplifies MVLs prepared in the presence of an acid or a base {see LL 6, and 7; Ans. 9 (“nothing in [Hartounian] indicate[s] that the process should be conducted in acidic conditions”); see generally Br. 7). In addition, Kim ’147 discloses that an acid “is essential for high encapsulation efficiency and controlled release rate of encapsulated molecules in biological fluids and in vivo” (LL 9; see generally Br. 7-8). Kim ’573 discloses liposomes containing cyclodextrin to encapsulate biologically active substances, thereby forming inclusion complexes that result “in a reduction in the rate of release of [active substance] from the 8 Appeal 2016-006917 Application 13/786,323 liposome compared to the rate of release of the same [substance] encapsulated in the absence of the cyclodextrin” (FF 10; cf Br. 19 (Appellants’ claim 1: “A formulation comprising [MVLs] . . wherein the formulation is substantially cyclodextrin free”) (emphasis added)). We recognize, but are not persuaded by, Examiner’s contention that Appellants’ “claims require the composition to be ‘substantially free of cyclodextrin’ the examiner points out that [Appellants’] specification does not provide a definition of the term as to what percentage appellants] consider[] as ‘substantially free’” (Ans. 8; cf. Br. 8 and 9-10). Nevertheless, Kim ’573 further exemplifies a method of producing liposomes, wherein the process comprises the use of an acid (FF 11). Examiner failed to explain how Hartounian, Kim ’ 147, or Kim ’573, taken alone or in combination, suggest a reason why a person of ordinary skill in this art would have prepared MVLs that contain a base salt of MTX. As discussed above, each of Hartounian, Kim ’147, or Kim ’573 suggest methods that require the presence of an acid (FF 3, 6, 7, and 9; see Br. 8). As Los makes clear, “a basic [addition] salt of methotrexate, for example, sodium methotrexate or potassium methotrexate [] cannot exist in an acidic environment” (FF 13). Further, while Hartounian suggests that “an acid or other excipient[, e.g. the ratio of slow and fast release neutral lipids,]” may be used to control the release rate of an active agent from a MVL and a preparative process that includes the presence of a base, Examiner failed to explain why Hartounian alone or in combination with Kim ’147, or Kim ’573 would have used a process that excluded an acid to specifically formulate a MVL that comprises a basic addition salt of MTX (see FF 3 and 7). To the contrary, Examiner finds that while Hartounian discloses “the use 9 Appeal 2016-006917 Application 13/786,323 of active agents or their salts,” Hartounian, Kim ’ 147, and Kim ’573 “do not teach the use of [a basic addition salt of MTX, such as,] methotrexate sodium or potassium salts specifically” (FF 14). For the foregoing reasons, the rejection over Hartounian, Kim ’147, and Kim ’573 alone or in combination is reversed. Examiner, however, relies on Heath to make up for the foregoing deficiency in Hartounian, Kim ’ 147, or Kim ’573, taken alone or in combination (FF 14). Specifically, Examiner relies on Heath to suggest the sodium salt of MTX (Ans. 4). Examiner, however, fails to appreciate that Heath discloses a preparative method that includes the sodium salt of MTX in an acidic composition (FF 15). Again, as Los makes clear, “a basic [addition] salt of methotrexate, for example, sodium methotrexate or potassium methotrexate [] cannot exist in an acidic environment” (FF 13). In this regard, we recognize Examiner’s assertion that “it is within the skill of the art of [the] highly developed [field] of chemistry to recognize that if one [is] using a salt in [an] acidic environment^ because] the pH ions are in higher amounts, the active agent will not exist in salt form and[,] therefore, the environment should not be acidic” (Ans. 9).13 Examiner failed to explain how Heath supports Examiner’s rationale as to what those of ordinary skill in this art would have known or done (see FF 15; cf. Ans. 9). In re Kahn, 441 F.3d 977, 988 (Fed. Cir. 2006) (“rejections on obviousness grounds cannot be sustained by mere conclusory statements; instead, there must be 13 Notwithstanding Examiner’s assertion that Los is based on “personal opinion,” Examiner appears to agree with Los’ statement that “a basic [addition] salt of methotrexate, for example, sodium methotrexate or potassium methotrexate [] cannot exist in an acidic environment” (see Ans. 8 and 9). 10 Appeal 2016-006917 Application 13/786,323 some articulated reasoning with some rational underpinning to support the legal conclusion of obviousness”). For the foregoing reasons, the rejection over Hartounian, Kim ’ 147, and Kim ’573 alone or in combination, taken with Heath is reversed. The combination of Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Walsh, Hendrix, Low, and Shirley, with or without Heath'. Based on Hartounian, Kim ’ 147, and Kim ’573 alone or in combination, taken with Walsh, Hendrix, Low, and Shirley, with or without Heath, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious “to administer [MVLs] containing folate since methotrexate causes side effects due to folate deficiency and administering folate as whenever the treatment involves methotrexate is known in the art as evident from Walsh and Hendrix” and further because “Low teaches folate receptor binding ligands can be encapsulated within the liposomes and Shirley teaches the use of [MVLs] for the delivery of folate” (Ans. 5-6). We are not persuaded. Examiner failed, however, to establish that Walsh, Hendrix, Shirley, and Low make up for the above discussed deficiency in Hartounian, Kim ’147, and Kim ’573 alone or in combination, with or without Heath (see FF 16; Br. 11). Therefore, the rejections over Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Walsh, Hendrix, Low, and Shirley, with or without Heath are reversed. 11 Appeal 2016-006917 Application 13/786,323 CONCLUSION OF LAW The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. The rejection of claims 1, 3-5, 7-15, 22, 23, and 76-84 under 35 U.S.C. § 103(a) as unpatentable over Hartounian, Kim ’147, and Kim ’573 alone or in combination is reversed. The rejection of claims 1, 3-15, 22, 23, and 76-84 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Heath is reversed. The rejection of claim 7 under 35 U.S.C. § 103(a) as unpatentable over Hartounian, Kim ’ 147, and Kim ’573 alone or in combination, taken with Walsh, Hendrix, Low, and Shirley is reversed. The rejection of claim 7 under 35 U.S.C. § 103(a) as unpatentable over the combination of Hartounian, Kim ’147, and Kim ’573 alone or in combination, taken with Heath, Walsh, Hendrix, Low, and Shirley is reversed. The rejection of claims 1, 3-5, 7-15, 22, 23, and 76-84 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over claims 59-78 of copending Application 13/786,368 is affirmed. 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. § 1.136(a). AFFIRMED-IN-PART 12 Copy with citationCopy as parenthetical citation