11845756 (P.T.A.B. Sep. 27, 2016)

Ex Parte New

Patent Trial and Appeal BoardSep 27, 2016

11845756 (P.T.A.B. Sep. 27, 2016)

UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 111845,756 08/27/2007 21839 7590 09/29/2016 BUCHANAN, INGERSOLL & ROONEY PC POST OFFICE BOX 1404 ALEXANDRIA, VA 22313-1404 FIRST NAMED INVENTOR Kent Christopher New 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. 007 6999-000002 9257 EXAMINER WANG, SHENGTIJN ART UNIT PAPER NUMBER 1627 NOTIFICATION DATE DELIVERY MODE 09/29/2016 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): ADIPDOC 1@BIPC.com PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE BEFORE THE PATENT TRIAL AND APPEAL BOARD Ex parte KENT CHRISTOPHER NEW Appeal2015-000810 Application 11/845,7561 Technology Center 1600 Before ULRIKE W. JENKS, JOHN G. NEW, and RYAN H. FLAX, Administrative Patent Judges. FLAX, Administrative Patent Judge. DECISION ON APPEAL This is a decision on appeal under 35 U.S.C. Â§ 134(a) involving claims directed to a method of reducing the chance of contracting a common cold using an ointment applied to the nose. Claims 1-13 and 16-30 are on appeal as rejected under 35 U.S.C. Â§ 103(a). We have jurisdiction under 35 U.S.C. Â§ 6(b). We affirm. 1 The Real Party in Interest is NUANCE HEAL TH, LLC. App. Br. 2. Appeal2015-000810 Application 11/845,756 STATEMENT OF THE CASE The Specification states, "[t]he present invention relates to virucidal compositions for the prevention of the spread of the common cold. Specifically, ... a virucidal ointment [used] in the nares of uninfected individuals to reduce the chance that they become infected with viruses such as rhinovirus, adenovirus, and parainfluenza virus." Spec. ,-i 4. Further, "[t]he invention may also be used in the nares of infected individuals to reduce transmission of viruses which cause the common cold." Id. The Specification states, "[t]he spread of common colds frequently occurs through hand-to-hand transmission of virus followed by self contamination with virus of the nasal or conjunctiva! mucosa." Spec. ,-i 7. "The proposed ointment contains a mixture of organic acids, with or without a surfactant in a carrier such as petrolatum or glycerin." Spec. ,-i 20. The "[ o ]rganic acids ... appropriate for use in the invention include: valeric acid, lactic acid, glycolic acid, pelargonic acid, aspartic acid, malic acid, and citric acid ... the invention [may] include any combination of one or more of these organic acids" and"[ o ]ne embodiment of the invention is malic acid (2%w/v) plus citric acid (2%w/v) in petrolatum." Spec. ,-i 25. The appealed claims can be found in the Claims Appendix of the Appeal Brief, with claims 1, 12, and 22 being independent claims. Claim 1 is representative and reads as follows: 1. A method of reducing the chance of contraction of a common cold, said method comprising: applying an amount effective to reduce the chance of contraction of a common cold of a virucidal ointment to one or both of a subject's nares; and 2 Appeal2015-000810 Application 11/845,756 reducing the chance of contraction of a common cold, the ointment comprising one or more organic acids and one or more carrier agents. App. Br. 25 (Claims App'x). The following rejection is on appeal: Claims 1-13 and 16-30 are rejected under 35 U.S.C. Â§ 103(a) over Hossain,2 Gem,3 Lorber,4 Ansel, 5 and Ballin. 6 Final Action 2. DISCUSSION We adopt the Examiner's findings of fact, reasoning on scope and content of the prior art, and conclusions set out in the Final Action and Answer. Any additional findings of fact noted below are only to highlight evidence of record. We conclude that the Examiner has established a prima facie case that the claims would have been obvious to a person of ordinary skill in the art over the cited prior art combination. 2 U.S. Patent No. 4,897,304 (issued Jan. 30, 1990 to Hossain et al.) (hereinafter "Hossain"). 3 U.S. Patent No. US 6,187,332 Bl (issued Feb. 13, 2001 to Gem et al.) (hereinafter "Gem"). 4 Bennett Lorber, MD, Perspectives - The Common Cold, 11 JGIM 229-36 (1996) (hereinafter "Lorber"). 5 HOWARD C. ANSEL ET AL., PHARMACEUTICAL DOSAGE FORMS AND DRUG DELIVERY SYSTEMS 372-78 (6th ed. 1995) (hereinafter "Ansel"). 6 U.S. Patent No. 3,297,207 (issued Jan. 10, 1967 to Ballin) (hereinafter "Ballin"). 3 Appeal2015-000810 Application 11/845,756 We address Appellant's arguments below. Appellant argues all claims together, therefore, all claims fall with claim 1.7 37 C.F.R. Â§ 41.37(c)(l)(iv). Claim Interpretation: "Nares" Appellant argues the claim language, "nares," must be interpreted to mean the external openings of the nose, to be distinguished from "the nasal mucosa." App. Br. 7-9 (citing HENDERSON'S DICTIONARY OF BIOLOGICAL TERMS (1979); MERRIAM-WEBSTER'S MEDICAL DICTIONARY (2010); and Spec. ,-i,-i 7, 29, and 22); Reply Br. 2. The Examiner determined that the broadest reasonable interpretation of "nares" includes the mucosa inside the nostrils. Ans. 4-5 (citing Spec. ,-i 22). The Patent Office, for more than 100 years, has applied the broadest reasonable construction standard in various proceedings. Cuozzo Speed Tech., LLCv. Lee, 136 S. Ct. 2131, 2145 (2016). During examination ofa patent application, pending claims are given their broadest reasonable construction consistent with the Specification. In re Am. Acad. of Sci. Tech Ctr., 367 F.3d 1359, 1364 (Fed. Cir. 2004). We find the claims themselves provide neither a satisfactory definition nor appropriate context by which to interpret "nares" or resolve the dispute over the claim language. Looking to the Specification, we likewise find the term "nares" not expressly defined therein and that it also 7 Although Appellant separately sets out claims 12 and 22 as patentable, the argument merely restates the claim language and presents no separate augments for patentability. "A statement which merely points out what a claim recites will not be considered an argument for separate patentability of the claim." 37 C.F.R. Â§ 41.37(c)(l)(iv). 4 Appeal2015-000810 Application 11/845,756 lacks context at the paragraphs cited by Appellant and the Examiner (see supra), and in general, to resolve the dispute. Appellant has not provided copies of the dictionary definitions he cites as evidence and, so, we look to other relevant and reliable resources immediately available to the Board. According to the OXFORD DICTIONARY OF BIOLOGY (7th ed. 2015): nares (nostrils) The paired openings of the nasal cavity in vertebrates. All vertebrates have external nares, which open to the exterior; in some species these are situated on a nose. Internal nares (or choanae) are present only in air-breathing vertebrates (including lungfish) and open into the mouth cavity. In mammals they open posteriorly, beyond the secondary palate. (http://www.oxfordreference.com/view/10.1093/acref/9780198714378.001.0 001/acref-9780198714378-e-2909?rskey=kzxoc7&result=3451, visited Sept. 19, 2016). According to DORLAND'S ILLUSTRATED MEDICAL DICTIONARY 346 and 1232 (32nd ed. 2012): naâ€¢res (na'rez) (sing. na'ris) [L.] [TAJ the external orifices of the nose; called also nostrils. anterior n, external n. nares. posterior n. the paired choanae; see choana (def. 2). [and] choâ€¢aâ€¢na (ko'g-ng) pl. cho'anae [L., from Gr. choane funnel] ... 2. [TAJ one of the pair of openings between the nasal cavity and the nasopharynx; called also posterior nasal aperture . ... It is apparent that the anatomical feature "nares" is not limited to the external features of the nose (the nostrils) as argued by Appellant, but also includes internal openings ( choanae) to the lower respiratory system. 5 Appeal2015-000810 Application 11/845,756 The nares', as defined above, relationship to nasal mucosa are illustrated by the NIH's U.S. NATIONAL LIBRARY OF MEDICINE, Medical Encyclopedia ("nasal mucosa," MedlinePlus.gov, https://medlineplus.gov/ency/imagepages/9674.htm, visited Sept. 12, 2016) (reproduced below): The above image shows the presence of human nasal mucosa throughout the internal nasal cavity, behind bridge of nose, above the palate, and between the afore-discussed external and internal nares. Based on the above-cited reference documents, the human nares and nasal mucosa are not mutually exclusive anatomical features, but are coterminous or at least substantially overlap. For these reasons, we find the broadest reasonable interpretation of "nares" includes both the external and internal nares and does not exclude the nasal mucosa. As determined by the Examiner, Hossain disclosed applying a virucidal composition, including citric and/or malic acids, to the nasal area (via an impregnated wipe or, alternatively, as a cream, lotion, lipstick, polish, mouthwash, or other cosmetic composition) and Gem disclosed 6 Appeal2015-000810 Application 11/845,756 applying a nasal spray comprising citric acid and a thickener to the nasal cavity, each to inhibit the spread of the common cold (Gem, expressly discloses prophylactic applications). Final Action 2-3; see also Hossain Abstract, 1:13-24, 4:6-10, Tables I-IV, 13:55-62; and Gem Abstract, 2:15- 67, 4:6-12. Therefore, Appellant's arguments concerning the interpretation of the claim language "nares" and that, in view thereof, the cited prior art combination fails to present a prima facie case for obviousness, are not persuasive. Further, one cannot show nonobviousness by attacking references individually, as Appellant attempts here, where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 426 (CCPA 1981). Alleged Evidence Attacking Hossain 's Disclosure Appellant argues that the Examiner's determination that Hossain's disclosed, applying an effective amount of a virucidal, organic acid composition to the nose/nares by wiping the nose with a tissue impregnated with the composition, is proven ineffective by experimental evidence. App. Br. 10-12. Because Appellant's contention overlooks that the similar- virucidal-composition of Gem is disclosed by that reference as applied so as to "adhere to the inside of the nose" (Gem 2:37--46), whether Hossain does or does not disclose actually applying its own virucidal composition to the nose/nares by wiping an impregnated tissue is not determinative. Again, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d at 426. In any event, Appellant's evidence and arguments submitted to 7 Appeal2015-000810 Application 11/845,756 disprove the Examiner's interpretation are flawed and, so, are not persuasive. In support of his argument, Appellant submitted a Declaration of Dr. New8 (hereinafter the "New Deel. 3")9 and with it a report titled "Evaluation of Residual Virucidal Activity on Pig Skin Surfaces - Rhinovirus," as evidence that wiping an impregnated tissue has an insignificant anti-viral effect as compared to a regular dry tissue and a "Swype shield [liquid] product." Dr. New described the experiment as follows: Specifically, the antiviral tissue (tissue paper with a center layer Impregnated with an organic acid (2% citric acid) and a surfactant (1 % sodium lauryl sulphate)) was wiped across a first area of pig skin surface, then a viral load was applied to the first area of pig skin surface, the virus was incubated on the skin surface for 10 minutes, and then the remaining amount of viral load was determined. New Deel. 3 iJ 6. We do not find this to be persuasive evidence. The Board has broad discretion as to the weight to give to declarations offered in the course of prosecution. See Velander v. Garner, 348 F.3d 1359, 1371 (Fed. Cir. 2003) ("[A]ccord[ing] little weight to broad conclusory statements [in expert testimony before the Board] that it determined were unsupported by corroborating references [was] within the discretion of the trier of fact to give each item of evidence such weight as it feels appropriate."). In re Am. Acad., 367 F.3d at 1368 (alterations in original). 8 Appellant's Declarant, Dr. Kent C. New, is of no known relation to Administrative Patent Judge New, sitting on the panel of this appeal. 9 During prosecution Appellant submitted three declarations by Dr. New, which are also submitted as evidence with the Appeal Brief. 8 Appeal2015-000810 Application 11/845,756 Appellant's experiment emulating Hossain' s antiviral tissue only exemplifies citric acid as the organic acid; however, Hossain discloses several alternative, effective organic acids (see, e.g., Hossain Tables I-IV), including malic acid, which the Declarant' s experiment itself identified as effective (see New Deel. 3 iii! 6-7). Also, the Hossain-surrogate-wipes included 2% citric acid, but Hossain disclosed "citric acid is effective at concentrations tested from 5% to 10% add-on." Compare New Deel. 3 iJ 6 with Hossain 11:14-16 and Tables I-IV. Therefore, Appellant's evidence does not support the contention that Hossain's disclosed impregnated tissues would not have been effective and Appellant's respective argument is not persuasive. Appellant's Argument Regarding Recited "apply a virucidal ointment to the nares, and reduce the chance of contraction of a common cold" Appellant argues: a typical nasal spray, such as in Hossain, has a viscosity of about 70 P. In contrast, an embodiment of the claimed invention which can be effectively applied to the nares has a viscosity of about 2000 P. The vast difference in viscosity is a further example of how the nasal spray of Hossain is very different from an embodiment of a product that would be applied to the nares. App. Br. 12. Because there is no viscosity limitation recited by claim 1, this argument is not persuasive. Moreover, as discussed above, Gem expressly disclosed adding thickener to its virucidal composition so it would "adhere to the inside of the nose" (Gem 2:37--46), which supports that viscosity is an optimizable variable, the manipulation of which was within the purview of those of skill in the art. "[D]iscovery of an optimum value of a result 9 Appeal2015-000810 Application 11/845,756 effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276 (CCPA 1980). Appellant's argument is unpersuasive. Appellant further argues that "in contrast to the claimed, 'reducing the chance of contraction,' the focus of Hossain is on reducing the transmission/spread of the common cold from an already infected party, not on reducing the contraction by a subject who may be without infection." App. Br. 12 (emphasis in original). This argument is not persuasive. Hossain disclosed a "method, composition and product for annihilating harmful respiratory viruses and inhibiting the spread of diseases, including the common cold." Hossain Abstract. Whether or not Hossain's primary focus was on already-infected subjects, this disclosure also renders "reduc[ing] the chance of contraction" obvious as it relates to the spread of the disease without regard to direction of infection. Moreover, Appellant's argument overlooks that the also-cited Gem expressly disclosed its virucidal "preparation [could be] used prophylactically or to treat an existing condition." Gem 4:9-10. Again, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d at 426. Appellant's argument is not persuasive. Alleged Evidence of Long Felt Need Appellant argues evidence of long felt need rebuts any prima facie case for obviousness and, in support, submits the first Declaration of Dr. New (hereinafter "New Deel. l") and the second Declaration of Dr. New 10 Appeal2015-000810 Application 11/845,756 (hereinafter "New Deel. 2") and, therewith as exhibits, a letter from the U.S. FDA and a clinical trial summary, respectively. App. Br. 16-20. "Evidence of a long felt but unresolved need tends to show non- obviousness because it is reasonable to infer that the need would have not persisted had the solution been obvious," but the evidence must show "that the claimed invention solved [the] long-felt need." WBIP, LLC v. Kohler Co., --- F.3d---, 2016 WL 3902668 *8-10 (Fed. Cir. July 19, 2016). Appellant argues the New Deel. 1 is evidence that the prior art is littered with references illustrating a desire to combat the common cold in various ways. App. Br. 16-18. We do not disagree that there has been a long felt need to prevent the common cold. Appellant also argues that the New Deel. 2 establishes the invention satisfied this long felt need. App. Br. 19-20. We do not find this evidence persuasive. Appellant's evidence describes a "clinical trial," a summary of which is provided as Exhibit 1 to the New Deel. 1, where 79 participants were enrolled over the course of two months (Feb. to Mar. 2011), two of those months also being the active study period (Feb. to Apr. 2011). New Deel. 2, Exhibit 1 at 4-5. The participants were adults with a history of contracting at least one YURI (viral upper respiratory infection) during "the last cold season." Id. The participants were each provided an antiviral nasal gel composed of 0.4% malic acid and 0.1 % sodium C 14-16 olefin sulfonate in a gel base of probanediol and Jaguar HP60, using Germaben II and Trisodium EDTA as preservatives. Id. at 2--4. The participants were instructed "to apply a small portion of the gel to their nares three times a day during cold 11 Appeal2015-000810 Application 11/845,756 season" and were "then surveyed via email once/week for 6-8 weeks to determine actual use of the nasal antiviral gel, side effects from use of the gel, and to report onset and severity of cold [and] flu symptoms." Id. at 4. Upon receiving a mixed set of surveys, some participants providing 8-9 surveys and some providing 6-7 surveys, the study reported 13 incidents of contraction of a YURI despite using the nasal antiviral gel (based on whether the participant reported nasal congestion or cough of at least "moderate severity"). Id. at 5-6. Based on this data, the Appellant concluded that the participants showed "an almost 70% reduction in the incidence of YURI compared to predicted incidence," even "[g]iven the complexity of factors which contribute to YURI, most of which are out of the control of the study sponsor and the study participants." Id. at 8. The study "was not a placebo- controlled study," but instead all participants used the active composition under investigation and the results were "compared to projections based on historical data." Id. In response to Appellant's evidence, discussed above, the Examiner determined, "there is no sufficient evidence[ to] support that the claimed invention satisfies the long felt need. Particularly, the small clinical study on the record cannot establish that the claimed invention satisfies the long felt need." Ans. 6. After considering the evidence presented, we find the weight of evidence supports the Examiner's determination. As Appellant notes, the study was not placebo controlled, but solely relied on comparing anecdotal evidence to historical norms, which the Appellant reports to be 2-3 episodes "during cold season (September 12 Appeal2015-000810 Application 11/845,756 through April) in adults." New Deel. 2, Exhibit 1 at 1. The anecdotal reporting relied upon for the study data was based on the imprecise definition of at least "moderate" symptoms of a cold or flu and it is unclear that the data collected across all participants can be relied on for consistency (the Appellant expressly notes that such symptoms could be caused by seasonal allergies, but the participants were not asked as a part of the surveys if this was the believed cause of reported symptoms). Id. at 5-6. We have considered, but are not persuaded by Appellant's evidence that the long felt need is satisfied by the invention. Because the evidence, i.e., the New Deel. 2 and its Exhibit 1, did not establish that the product tested was within the scope of the claimed invention (e.g., we have no evidence equating the tested gel to the claimed ointment) and did not rely on sound scientific method (e.g., relied on anecdotal evidence, no placebo control, admittedly imprecise survey, limited number of participants, no evidence of controlling other potentially and admittedly-complex result- effecting variables, etc.), we find it insufficient to establish that the invention has satisfied the long felt need for preventing or reducing the chance of contracting the common cold. Although the Examiner did not expressly determine that Appellant's clinical research was unreliable because it compared the test group to a historical norm (rather than to a placebo control group), Appellant argues that such a study is "a common type of clinical study." Reply Br. 6. Appellant, however, provides no evidence to support this allegation. It is well settled that arguments of counsel cannot take the place of factually 13 Appeal2015-000810 Application 11/845,756 supported objective evidence. See, e.g., In re Huang, 100 F.3d 135, 139--40 (Fed. Cir. 1996); In re De Blauwe, 736 F.2d 699, 705 (Fed. Cir. 1984). According to the FDA, Appellant is correct, but only to a degree: (V) Historical Control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (for example, certain malignancies) and studies in which the effect of the drug is self-evident (general anesthetics, drug metabolism). Robert Temple, M.D., Design of Clinical Trials, FDA 's Clinical Investigator Course 25-31 (Nov. 8, 2011) (http://www. fda. gov I downloads/Training/ClinicalinvestigatorTrainingCours e/UCM283377.pdf, visited Sept. 14, 2016) ("[m]any examples of misleading [historical controls tests]; [urging] great care in relying on one."). The Appellant's study does not fall into one of the categories the FDA recommended for historical controls because the effect of the Appellant's invention is not "self-evident" and the disease studied does not have a "high and predictable mortality." For the reasons discussed above, we find that Appellant has not overcome the Examiner's prima facie case for obviousness with evidence of long felt need, satisfied by the invention. 14 Appeal2015-000810 Application 11/845,756 Alleged Evidence of Skepticism by Experts Appellant argues "evidence that the inventive idea has been met with expressions of disbelief by experts" overcomes the Examiner's prima facie case for obviousness. App. Br. 20. We are not persuaded. As evidence of skepticism, Appellant submits New Deel. 1 and Exhibit 1 thereto, which is an undated letter from the FDA to the Appellant/Declarant. App. Br. 20; New Deel. 1, Exhibit 1. The statement in the letter to which Appellant points reads as follows: Clinical Response. Based on the information provided, we do not see specific safety concerns at this time. We are more concerned that the product will not demonstrate any clinical efficacy. New Deel. 1, Exhibit 1 at 2. We do not read this statement as expressing skepticism for the invention. The FDA is responsible for ensuring drugs intended for human use are safe and effective. The FDA's statement above, rather than indicating it did not believe the invention would work, was an indication it was less concerned with safety because there was "extensive published literature which includes animal and human safety studies" relating to the product's components, but was more concerned with clinical efficacy in view of Appellant's previously demonstrated in vivo activity in a finger pad study having been determined not sufficient for such an efficacy claim and because no clinical data had been submitted by Appellant. See id. at 1-2. For the reasons above, we find Appellant has not overcome the Examiner's prima facie case for obviousness with evidence of skepticism of experts regarding the invention. 15 Appeal2015-000810 Application 11/845,756 CONCLUSION For the above reasons, we find the evidence of record supports the Examiner's determination that the claims would have been obvious over the cited prior art combination and Appellant has not presented persuasive evidence to rebut this determination. We affirm the obviousness rejection. SUMMARY The rejection of claims 1-13 and 16-30 under 35 U.S.C. Â§ 103(a) over Hossain, Gem, Lorber, Ansel, and Ballin 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. Â§ l.136(a). AFFIRMED 16 * * Notice of References Cited Documeni Number Country Code-Nun1ber-Kind Code A US- B US- c US- D US- E US- F US- G USÂ· H US- US- J US- K US- L US- M US- N 0 p Q R s T Document Number Country Code-Number-Kind Code Date MM-YYYY Date MM-YYYY Application/Control No. l li845,756 Examiner U.S. PATENT DOCUMENTS Name FOREIGN PATENT DOCUMENTS Couniry NON-PATENT DOCUMENTS Name Appiicant(s)/Patent Under Patent Appeal No. 2015-000810 Art Unit [ l 627 I Page 1 of1 Classifica1ion Classifica1ion * Include as applicable: Au1hor, Tille Date. Pub!isher. Edition or Volume, Pe1iinen1 Pages) u Doriand's Elustrnted Medical Dictionary 32nd Edition v FDA's Clinical Investigator Course w Oxford Reference -- Nares x MedlinePius -- Nasal mucosa *!\copy of this t"eference :snot be1n9 furnished wnn tn:s Off;ce act:on (See MPEP Â§ 707.05(a).) Dates in MM-YYYY forrnat are publication dates. Classif:cations n1ay be US or foreign. U.S. Pa.tent and Trademaok Oftice PT0-892 (Rev 01-2001) Noiice of References Cited Part of Paper No. WORD IN fv1EDIC!NE FOR OVER 110 YEARS EI.JSEVIER SAUNDERS 1600 fohn F. Kennedy Blvd .. Ste lSOO . Philadelphia, PA 19103-2899 DORLAND'S ILLUSTRATED MEDICAL DICTIONARY 32nd edition ISBN: 978-1-4160-6257~8 (Standa 978-1-4160Â·Â·6256-1 (Delu 978-0-8089-2418-0 (Internatior. Copyright (Q 2012, 2007, 2003, 2000, 1994, 1988, 1985', 1981, 1974, 1965', 1957, 1951, 1947, 1944, 1941, 1938, 1935, 193Z, 1929, 1927, 1923, 1921, 1919, 1917, 1915, 1913, 1911, 1909, 1906, 1903, 1901, 1900 by Saunders, an imprint of Elsevier Inc. No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recordi1 or any information storagÂ·e and retrieval S)>5tem, without permission in writing from the publisher. 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In using such information or methods they should be mindful of their own safety and the safoty of others, including pax1ies for whom they have a professional responsibility . ...................... .... Witl1 respect to any drug or.pharmaceutical product~Â·identified;Â·rea:, PhD Lexicogmpher: Jefferson Keith, MA Assistant Lexicographer: Michelle A. Elliott, MA Pt1bfifbing Seruices .UJ.nager: Patricia Tannian Senior Project M"anager; Linda Van Pelt Design Direr:tfon: Steve Stave Printed in tl1e United States of America Last digit is the print number: 9 8 7 6 5 4 3 2 ,...--------------Â·Â·Â·Â·Â·Â·------ Working together to grow libraries in developing countries www.elsevier.com j www.bookaid.org I www.sabre.o.rg naprapath .............................................................................. nasolabial napâ€¢raâ€¢path (nap'r;:i--path) a practitioner of naprapathy. naâ€¢prnpâ€¢aâ€¢thy (n;i-prap';i-Â·die) [Czech naprttvit to correct + -pathy] a system of therapy employing manipulation of connective tissue Oigaments, muscles, and joints) and dietary measures; sajd to facilitate tbe recuperative and regenerative processes of the body. naprapath'ic _adj Nap-reâ€¢lan (nap1r;i-lan) trademark for a preparation of naproxen sodinm. Naâ€¢proâ€¢syn (nap'r::i-sin) trademark frlr pi-eparations of naproxen. naâ€¢proxâ€¢en (n;i-prollepâ€¢sy (nahr'ko-lep"se) [narco- + Gr. lepris a taking hold, a sei- zure] [DSM-IV] recurrent, uncontrollable, brief episodes of sleep, often associated witll hypnagogic or hypnopompic hallucinations, cataplexy, and sleep paralysis. Called also Gelinerm syndrome and p1woxysm,1l sleep. riarâ€¢coÂ·lepâ€¢tic (nahr'"'ko-lep'tik) L pertainingÂ· to, characterized by, or producing narcolepoy. 2. an agent that produces narcolepsy. 3. a person with narco!epsy. - narâ€¢coâ€¢ma (nahr-ko'ma) a stuporous state produced by narcotics. narâ€¢cose (nahr'kos) stuporous. narâ€¢coÂ·sine (nahr'ko-sen) noscapine. narÂ·coâ€¢sis (nahr-ko'sis) [Gr. narkosis a benumbing] a nonspecific and reversible depression of fonction of t11e central nervous system marked by stupor or ir1sensibility, produced by opioid drngs and certain otht~r substances. narcosis marked by complete unconsciousness, amnesia, and basal n. analgesia. Â· Nasion Nasâ€¢myth membrane (nas1mith) [Alexander Nasrriyth, Scottish dental surgeon in London, died 184Â·7] primary (enfilnel) cuticle. NAS-NRC National Academy of Sciences--National Research Council. oas{olÂ·Â· tlle nose. [L nmus nose] a combining form denoting relationship to (na"zo--an'uÂ·;il) pertaining to the nose and the ma.'(]]fary antrurn (sinus). naâ€¢soâ€¢anâ€¢triâ€¢tis (na"zo-an-tri'tis) rhinoantritis. naâ€¢soâ€¢anâ€¢trosâ€¢toâ€¢my (na"zo-an-tros'ta-me) surgical format1on of a nasoantral Â·window for drainage of an obstructed maxi!J.ary sinus. naâ€¢soâ€¢b1Â·onâ€¢chiÂ·al (na"zo-brong'ke-;J]) pertaining to the nasal cavities and the bronchi. carbon dioxide n. respiratorv acidosis .. - Â· naâ€¢soâ€¢cilâ€¢iâ€¢ary (na"zo--sil'e-ar"e) pertaining to or 3.ffecting the eyes, nitrogÂ·en n. a state resembling drunkenness, with euphoria and dis-- d "' brow, an root of the nose, as the nasociliary nerve. orientation, seen in divers below about 30 meters (100 feet) Â·who are breath- ing compressed air, because of the high nitrogen content of air; some of naâ€¢so-ethÂ·moiÂ·dal (11a"zo-eth-moi1d::il) ethmonasaL the nitrogen enters the bloodsuÂ·eam and acts as a narcotic. Somedmes naÂ·soÂ·fronâ€¢tal (na"zo-fron'tdl) pertaining to the nose or other ::12sal popularly called nipture ~f the deep. structures and the forehead or the _frontal bone; called also frontonastd narâ€¢coâ€¢stimâ€¢uâ€¢iant (nahr"ko-stirn'u--1;,nt) having both narcotic and naâ€¢soâ€¢gasâ€¢'Mc (na"zo-gas'trik) pertaining to the nose and stomach, stimulant properties. as in (nasogastric) aspiration of the stomach's contents. narâ€¢cotâ€¢ic (nahr-kot'ik) [Gr. nr;rkiitikos benumbing, deadening] 1. per- naâ€¢soâ€¢laÂ·biâ€¢al (na"zo-la'be-;)l) [naso- + labial) pert3ining to the nose taini."l.g to or producing narcosis. 2. an agent that produces insensibility and lip. 1232 ~~------------------- p-chlorophenol ......................................................................... chocolate p-chloâ€¢roâ€¢pheâ€¢nol (klor1'o-fe'nol) parachlorophenol. cllloâ€¢rcÂ»xyÂ·ieâ€¢nol (k:lor."o-zi'l;i-nol) an antibacterial active chiefly chloÂ·.rnÂ·phyll (klor'o-fil) [cbloro- + Gr. phyllon leaf] any of a group of against streptococci; used mainly as a skin disinfectant. green magnesium-containing porphyrin derivatives occurring in ail photo- chlor'â€¢phenâ€¢irâ€¢amine (l occurs c. maleate [USP] the ma!eatl: salt of chlorpheniramine, used in diÂ· in all organisms exhibiting aerobic photosynthesis (green plants, algae, and treatment of allergic rhinitis, allergic conjunctivitis, and cutaneous inan:: cyanobacteria), chlorophyll b in higher plants, chlorophylls c.1 and <;2 in festations of allergic reactions, and as an ingredient in some cough and cold diatoms and brown algae, and d1lorophyll d in. red algae. preparations; administered orally or by intramuscular, intraveno1ls, or sub. Bacterioci'Jorophylls occur in bacterfa e..xhfoiting anaerobic photosynthesis. cutaneous injection. Preparations of water-soluble d1lorophyll salts are nsed as deodorizers; see c. polistfrex su[fonated styrene-divinylbenzene copolymer coinpiex chlorophyllin, with chlorpheniramine, having the same actions as the base; used ;il chloâ€¢roâ€¢phylolin (klor'o-filÂ·-in) any of the waterÂ·Â·soluble salts. obtained cough and cold preparations, administered orally. Q by alkaline hydrolysis of chlorophyll with replacement of the methyl and c. tannate the tannate salt of chlorpheniramine, having the same ac- phytyl ester groups by sodium or potassium; preparations of the salts are t1ons as the base; used in cough and cold preparations, administered orally. applied topically for the deodorization of skiri lesions and administered chlorâ€¢proÂ·maâ€¢:r.ine (klor-pro'm;i--zen) [USP] a phenothiazine deriva- orally to deodorize ulcerative skin lesions and t.1-ie urine and feces in colos- rive, used as an antiemetic and tranquilizer, and for the management of tomy, ileostomy, and incontinence, severe behavior disorders in children; administered rectallv. c. copper complex a chlorophyllin in which copper has replaced the c. hydrochloride [USP] the hydrochloride salt of -clilorprornazine. porphyrin magnesium; it is the most widely used form of chlornphyllin. used as an antinsychotic and antiemetic, to control presmgical apprehen: ChloÂ·roÂ·phylolum (k!o-rof"f--fam) a genus of mushrooms of the family sion, to control the maillc phase of bipolar disordet, t0 treat intractible Agaricaceae. C. ma{yb' ditc.r is similar in appearance to species ofAmanita and hiccups, acute intermittent porphyria, and tetam1s, and for the management contains smail amount' of amatoxins, so that it ocrn;,ionally causes mush- of severe behavior disorders in childten. room poisoning (see under poisoning). chlorâ€¢proâ€¢paÂ·mide (klorÂ·Â·pra1p;,-m!d) [USP] a sulfonylurea cr>m- chloÂ·roÂ·pia (klor-op'e-;i) chioropsia. pound used as a hypoglycemic in the treatment of type 2 diabetes mellitu& d administered oraUv. ' Chloâ€¢ropâ€¢iÂ«lae (klor-op'!-de) a family of small to minute flies (or er Â· Diptera); two medically important genera. are Hippe/ates and S~'Jhu:ncuiina. ch!orâ€¢pyâ€¢riÂ·fos (k:lor-pi'r!-fos) an organophosphorns insecticide used chloâ€¢roâ€¢plast (k:lor'o-piast) [chloro- + -plart] any one of the. chloro- to disinfect plants; accident.al overexposure can cause extrapynmidal effects Pk.rll-bearing bodies of plant cells. such as salivation, tremors, dizz.iness, and eventually seizures, coma, ?.nâ€¢roâ€¢pmâ€¢caine hyâ€¢droÂ·chloÂ·ride (klor110-pml.'iin) [USPJ a)ocal administered orally or intravenously, or applied topically to the skin or â€¢ anesthetic used in minor and general surgery for infiltration anest.f-iesia, conjunctiva. Â· Â· Â· Â· Â· Â·Â·Â· Â· -â€¢â€¢ Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â· Â·Â·Â·Â·Â·Â·Â·field block,Â· Bier -block, regional ne.ive block,Â· arid caudal .and lumbar .epidn" Â· Â· Â· Â· Â· Â· Â· Â· chtorâ€¢thalâ€¢ i â€¢doneÂ·Â·Â· -(klor"thalT-don) Â·Â·Â·[USP]Â·Â·Â· Â·aÂ·Â· Â·sulfonamide Â·Â·derivativeÂ·Â· ral a.'lesthesia; used also for h1filtration and nerve block in dental that has a_ different chemical stn1cture from but the same actions 3;, the procedures. thiazide diuretics, used in the treatment of hvpertension and edema: ad- cMoâ€¢rnâ€¢proâ€¢pyâ€¢lene oxÂ·ide (klo11ro-pro1p;i-len) epichlorohydrin. mini5tered orally. ' ' ch!oâ€¢ropÂ·sia (ldor-op'se-;i) [cbloro-- + -opsiri) a chromatopsia_ in which Chlor-Triâ€¢meÂ·ton (klor-tri1ma-ton) trademark for preparations of all objects seen appeat to have a greenish tinge, a symptom of digitalis chlorphet1iramine rnaleate. poisoniilg-. chlorâ€¢urnâ€¢sis (klor"u-re'sis) [chlor- + -u.resisj excretion of excessive. Chlorâ€¢op-tfo (klor-op'tik) trademark for preparations of cbloram- chlorides in the mine; called also chluriduria and byperchlorlduri.1, phenicoL chlorâ€¢uretÂ·ic (l.i'ived from or containing trivalent chlorine, as in the cell. Cf, am,migote, epimttstigote, opii-tharnardgote, promastigote, and chiorous add, HCl02; a term used to distinguish those compounds which trypomnstigote. contain a larger proportion of chlor'..ne than the chloric compounds, and Cftoâ€¢aâ€¢noâ€¢t.aeâ€¢ni.a (koÂ·Â·a"no-te'ne-;i) [Gr. cboane fUllllcl + taenia (def. forming salts knovm as ch!orites. 2)] a genus of tapeworms. C. infimdi'bulmn is a common but nonpatho- chloâ€¢rnus acâ€¢id (klo/;is) a weak inorgaillc acid, HClOz. genie para.site of chickens and turkeys. chloâ€¢roâ€¢viâ€¢nylÂ·diÂ·chloâ€¢roâ€¢arÂ·slne (kJmJ'oÂ·-vin";,l-di-klor"o-ahr'sin) chocâ€¢oâ€¢late (chok';i-lat) [Nahmitl xocolatfJ L [NF] in pharmacy, a lewisite. powder prepared from roasted, cured ripe seeds of Tbeobnrrn11 m~Â·aa, chloâ€¢roxâ€¢ine (klor-ok'sen) a synthedc antibacterial, used in t:'ie topical which contains caffeine and theobrornine; used as a flavor in phannaceu~csl treatment of dandruff and seborrheic dermatitis of tl1e scalp. preparations (see also cfxJcol.ate syrup, under syrup), 2. a confection made 346 1111 ~""""""~ ~"""'' i\ ~''''""' ~ ~ ~~ I'"\ ~ l,,,~J ~ ~ (''''~ ~ "1 Â§'~ ~ ~ ~ ~-'""Â§ ~~ ~ ~ ~~..$' ~~~ ~ ~ '~" ~ :S-~'~ #''~ ~'~ * ~,-''1 \I ~*~ Â§'~ ~'~ ~~t~ ~~~ Â§_S-..;: ~ . ~~ ~ ~ ~~ ~'~ ~~ l ~ ~''''1 * ~'""~ ~~ ~ [ ~ ~,,,,,~ * l ~ ~ \Â§_ ~ ~ ~ ~ ~~ ~~ ~ ..... ~ Â§ ~ ~ ~~ ~~.._$~~"* ~ ~"''~ ~"''~ ~ ~,# ~,~$ ~J ~"''"Â§! ~ ~"-$ \..~~ ,,, ..... ~ Cosponsored by FDA js Office of Critical Path Programs (OCPP) and The Clinical Trials Transformation Initiative (CTT!) Food m1d Drug Ad111inistration 1111 Design of Clinical Trials Robert Temple, M.D. Food and Drug Administration November 8, 1111 (V) Historical Control. The results of treatment with the test drug are compared with experience historically derived from the adequately documented natural history of the disease or condition, or from the results of active treatment, in comparable patients or populations. Because historical control populations usually cannot be as well assessed with respect to pertinent variables as can concurrent control populations, historical control designs are usually reserved for special circumstances. Examples include studies of diseases with high and predictable mortality (for example, certain malignancies) and studies in which the effect of the drug is self-evident (general anesthetics, drug metabolism). lt=i>Y,& II II ~ ~ ~ ~,,~ ~ ~,,,,.._i ~ ~~ ~ ~ ~ ~~"<' ~ Retrospective Unblinded ~ ~@~ ~ ~ ~ I 1Â· ~f~ ~' ~@ ~ ~ l ~ ~ ~ \ Selection bias very hard to avoid yÂ·~ ~ % ~@~-"~ I ) ~~ ~ ~ ~ . .Â§ ~ ~ ~ Past experience, other non-random experience Baseline (patient as own) control is a kind of historical control (assume what would have happened). 1111 Critical Reference - Sacks, Chalmers, Smith Am J. Medicine (1982); 72:233-240. Comparison of RCTs and HCTs for same disease Always 1. RCT less favorable than HCT 2. Reason was that the historical control was worse than the randomized control (selection bias) 3. Not possible to "adjust" the difference Many examples of misleading HCTs; great care in relying on one. Addressed in ICH E-10 lt=i>Y,& Table I - Conclusions of RCTs and HCTs on Six Therapeutic Questions ----- 1-ICT Matched or Adjusted for RCT All Trials Proo-no~t-ic F:::ictor~ - __ C' ________ - ------ Question Effec- Ineffec- Effec- Ineffec- Effec- lneffec- Studied tive tive tive tive tive tive Cirrhosis with 6 14 12 6 2 1 Varices Coronary Artery 1 7 16 5 9 1 Surgery Anticoagulants l 9 5 1 3 1 for Acute Myocardial Infarction 5-FU Adjuvant for 0 5 2 0 2 0 Colon Cancer BCG Adjuvant for 2 2 4 0 4 0 Melanoma DES for Habitual 0 3 5 0 1 0 Abortion TOTALS 10 40 44 12 21 3 II l:!f#.1'_..., II ! w ~ oL ___ . I} l ;:i; ~ -1llo 'I~lll!J:: L SURl/lli,\I:. Of TtEATÂ£0 AND ;;u1n11ol. ~~!lWf'S tl'i c:tun:u TUAts 01' SHUNT Table IV Pooled Survival in Clinical Trials of Medical Versus Surgical Treatment of Coronary Artery Disease No. No. Percent Survival Studies Patients 1 YR 2YR 3YR 4YR RCT 9 18,861 Surgical 92.4 89.6 87.6 85.3 Medical 93.4 89.2 83.2 79.8 HCT 6 9,290 Surgical 93.0 92.2 90.9 88.3 Medical 83.8 78.2 71.1 65.5 Sur2"ical Adiusted* 93.7 92.5 91.2 87.4 -- - '--' ~ Medical Adjusted* 88.2 82.2 70.9 67.7 *Adjusted to have the same proportion of patients with one-, two- and three- vessei disease as in the RCTs. 1111 Fulminant Hepatitis B - Australia AG Treatment History Gocke observed 9 consecutive cases of acute fulminant hepatitis, all fatal despite exchange Tx, steroids, supportive care Then, 8 hepatitic coma patients given same Rx plus anti-Australia antigen serum, with 5/8 survival Considered accepting data but concluded it could represent better care, earlier Rx Therefore RCT in severe hepatitis. Hyperimmune globulin vs. normal serum globulin [Result - no effect] lt=i>Y,&