Carlos Alberto. Guzman et al.Download PDFPatent Trials and Appeals BoardJul 26, 201913848936 - (D) (P.T.A.B. Jul. 26, 2019) 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. 13/848,936 03/22/2013 Carlos Alberto Guzman 03100215CON 1788 30743 7590 07/26/2019 W&C IP 11491 SUNSET HILLS ROAD SUITE 340 RESTON, VA 20190 EXAMINER ZEMAN, ROBERT A ART UNIT PAPER NUMBER 1645 MAIL DATE DELIVERY MODE 07/26/2019 PAPER 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. PTOL-90A (Rev. 04/07) UNITED STATES PATENT AND TRADEMARK OFFICE ____________ BEFORE THE PATENT TRIAL AND APPEAL BOARD ____________ Ex parte CARLOS ALBERTO GUZMAN and PETER MÜHLRADT ____________ Appeal 2018-0054711 Application 13/848,9362 Technology Center 1600 ____________ Before DONALD E. ADAMS, ULRIKE W. JENKS, and JOHN E. SCHNEIDER, Administrative Patent Judges. ADAMS, Administrative Patent Judge. DECISION ON APPEAL This Appeal under 35 U.S.C. § 134(a) involves claims 12–22 (Final Act.3 2). 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 REVERSE. 1 The record includes a transcript of the Oral Hearing held July 2, 2019. 2 Appellants identify “Helmholtz-Zentrum fuer Infektionsforschung GmbH” as the real party in interest (Appellants’ November 8, 2017 Appeal Brief (App. Br.) 3). 3 Examiner’s May 31, 2017 Final Office Action. Appeal 2018-005471 Application 13/848,936 2 STATEMENT OF THE CASE Appellants’ disclosure “relates to the use of a lipopeptide or lipoprotein as adjuvant in therapeutic or prophylactic vaccination, especially via the mucous membranes, i.e. as mucosal adjuvant” (Spec. 1: 4–7). Appellants’ claim 12 is representative and reproduced below: 12. A method of vaccinating an animal or human in need thereof, comprising the steps of: providing said animal or human, via mucous membranes of said animal or human, with an antigen; and providing said animal or human, via mucous membranes of said animal or human, with an adjuvant in the form of a lipopeptide or lipoprotein of the structure (I) where R1 and R2, which may be identical or different, are C7-25- alkyl, C7-25-alkenyl or C7-25-alkynyl, X is S, O or CH2, R3 and R4 are independently of one another H or methyl and Y is a physiologically tolerated amino acid sequence which consists of 1 to 25 amino acid residues and is not immunogenic per se in the species used, and the asymmetric carbon atom marked with * as the absolute R configuration, according to the Cahn-Ingold-Prelog rule, when X is S (sulfur). (App. Br. 30.) Appeal 2018-005471 Application 13/848,936 3 Grounds of rejection before this Panel for review: Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’2424 and Foss.5 Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’1106 and Foss. Claims 12–22 stand rejected under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’977 and Foss. Claims 12, 13, 15, 16, 20, and 22 stand rejected under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Mühlradt ’242 and Foss. Obviousness: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness? FACTUAL FINDINGS (FF) FF 1. There is no dispute on this record that each of Mühlradt ’242, Mühlradt ’110, and Mühlradt ’97 “teach a [MALP–2] peptide that would be encompassed by the claims” (Oral Hearing Transcript8 3: 18–20; see 4 Muhlradt, US 6,573,242 B1, issued June 3, 2003. 5 Dennis L. Foss et al., Role of Macrophage Cytokines in Mucosal Adjuvanticity, 41 ADVANCES IN VETERINARY MEDICINE 83–104 (1999). 6 Mühlradt, WO 98/27110, published June 25, 1998. 7 Peter F. Mühlradt et al., Isolation, Structure Elucidation, and Synthesis of a Macrophage Stimulatory Lipopeptide from Mycoplasma fermentans Acting at Picomolar Concentration, 185 J. EXP. MED. 1951–58 (1997). 8 Transcript for Oral Hearing held July 2, 2019. Appeal 2018-005471 Application 13/848,936 4 generally Ans.9 3 (discussing Mühlradt ’242); Ans. 4 (discussing Mühlradt ’110); Ans. 5 (discussing Mühlradt ’97); see Spec. 8: 16–17 (“The lipopeptides of [Appellants’] . . . invention are also referred to as MALP, namely as ‘macrophage-activating lipopeptides’. These include . . . MALP–2”)). FF 2. Mühlradt ’242 discloses a composition comprising a peptide within the scope of Appellants’ claimed invention “together with a conventional carrier and/or adjuvant” (Mühlradt ’242 1: 64–67). FF 3. Mühlradt ’242’s composition “can be used for stimulating the synthesis of antibodies . . . for activating [macrophages], . . . or as a vaccine adjuvant (admixture with a vaccine)” (Mühlradt ’242 1: 67 – 2: 7; see also Mühlradt ’242 4: 39–47 (Mühlradt ’242 discloses a method of stimulating the synthesis of antibodies comprising the step of administering a composition for activating macrophages comprising a peptide within the scope of Appellants’ claimed invention together with: (a) an excipient or additive or excipient and in admixture with a known vaccine to humans or animals or (b) a conventional excipient or additive or excipient and additive in admixture with a vaccine); see Mühlradt ’97, Abstract; Ans. 3 (discussing Mühlradt ’242); Ans. 4 (discussing Mühlradt ’110); Ans. 5 (discussing Mühlradt ’97)). FF 4. Mühlradt ’242’s peptide “has the property of stimulating macrophages of mice and humans to release cytokines and prostaglandins, with all the consequences of indirect stimulation of T and B lymphocytes” 9 Examiner’s March 8, 2018 Answer. Appeal 2018-005471 Application 13/848,936 5 (Mühlradt ’242 2: 58–61; see Ans. 3 (discussing Mühlradt ’242); Ans. 4 (discussing Mühlradt ’110)). FF 5. Examiner finds that each of Mühlradt ’242, Mühlradt ’110, and Mühlradt ’97 fail to disclose, inter alia, a peptide, within the scope of Appellants’ claimed invention, as a mucosal adjuvant and relies on Foss to make up for this deficiency (Ans. 3–5). FF 6. Foss discloses: The mucosal immune system is in constant contact with vast numbers and varieties of antigens, both living and dead, dangerous and benign. The ability to selectively mount appropriate immunity to potentially harmful antigens and organisms, while at the same time tolerating beneficial ones, is essential to the maintenance of homeostasis. This conflict in function is especially problematic in the immune system of the intestinal tract (gut-associated lymphoid tissue or GALT), where immunity to pathogens must coexist with a need to control inflammatory responses to the lumenal flora and dietary antigens. Understanding the molecular basis of this decision will aid the rational development of mucosally delivered vaccines. (Foss 83–84.) FF 7. Foss discloses that “[t]here are a wide variety of potential mechanisms for adjuvants to enhance mucosal immunity,” including “[a]lterations in delivery of antigen to the GALT,” “[e]ffects on antigen presentation,” “B-cell antibody isotype switching,” “[c]ytokine production by antigen-specific lymphocytes, induction of Th2 phenotype,” and “[l]ymphocyte proliferation” (Foss 92–93 (emphasis omitted)). FF 8. Foss discloses that the “[d]elivery of protein antigens to the GALT can result in immunity or oral tolerance depending on the circumstances of the encounter,” wherein “[o]ne mechanism by which mucosal adjuvants can Appeal 2018-005471 Application 13/848,936 6 affect these circumstances is by the induction of macrophage cytokines, including IL-1 and IL-12” (Foss 98 (emphasis added); see id. at 99 (“the mucosal adjuvanticity of [cholera toxin (CT)] involves a variety of mechanisms,” including “a role for the induction of the macrophage cytokines IL-1 and IL-12”)). FF 9. Foss discloses: There are significant differences between species in the adjuvanticity of CT and [cholera toxin’s B subunit (CT-B)]. In humans oral CT-B is generally considered to be immunogenic. Oral cholera vaccine containing CT-B results in systemic and local (intestinal) antibody response . . . , but inconsistent response in distant mucosal sites including vaginal washes . . . or in saliva . . . and no detectable secretory antibodies in breast milk. . . . While immunogenic orally in humans, CT-B shows no adjuvant effect for the coadministered, whole-cell portion of the cholera vaccine as measured by vibriocidal antibodies. . . . In contrast to oral administration, intranasally administered CT- B results in systemic (serum) as well as distant mucosal (vaginal) anti-CT-B responses. (Foss 86; see id. (“species differ in the mucosal immunogenicity and adjuvanticity of CT-B and CT”).) FF 10. Foss discloses that although “parenterally administered [keyhole limpet hemocyanin (KLH)] resulted in a robust [immune] response,” “[i]ntragastric administration of . . . [KLH, alone,] results in little or no response,” KLH in combination with “CT results in both local (intestinal wash) and systemic (serum) anti-KLH IgA and IgG” (Foss 87). FF 11. Guzman declares that Foss “focused [its] . . . work in the study of a single and well-established[,] at the time[,] mucosal adjuvant. Thus, the Appeal 2018-005471 Application 13/848,936 7 assumptions made cannot be extrapolated to adjuvants in general and/or mucosal adjuvants in particular” (Guzman Decl.10 ¶ 5). FF 12. Guzman declares that Foss specifically mentioned a long list of “potential” underlying mechanisms (i.e. activation of macrophages is just one of the multiple proposed mechanisms), which might explain the adjuvanticity of the tested compound/toxin. The authors are not providing in this publication solid experimental evidence, which can be useful for ruling out or conforming the specific contribution of any of the hypothesized mechanisms for the adjuvant effect. Thus, by and large, all the proposed mechanisms represent as a whole just an informative compendium of potential mechanisms of action, for which backing evidence is overdue (i.e. just putative roles are described or associations are made). None of them can be seriously proposed as the underlying mechanism of adjuvancity in general, and even less as the mechanism explaining the mucosal adjuvanticity of cholera toxin, A-B moiety toxins or their derivatives and/or other compounds exerting activity as mucosal adjuvants. (Guzman Decl. ¶ 5; see id. (Guzman declares that “not every macrophage stimulating molecule is a ‘mucosal adjuvant’”).) FF 13. Guzman identifies several mucosal adjuvants and declares that “there are no overall macrophage-driven mechanisms responsible for mucosal adjuvancity, that specific interactions with macrophages could be dispensable and that several distinct mechanisms can be in part leading to mucosal adjuvanticity” (Guzman Decl. ¶ 5). FF 14. Guzman declares that “it is not a reasonable expectation that molecules which are able to activate macrophages are generally acting as mucosal adjuvants” (Guzman Decl. ¶ 5). 10 Declaration of Carlos A. Guzman, signed July 4, 2011. Appeal 2018-005471 Application 13/848,936 8 FF 15. Guzman declares that every compound, before it can be determined to be an adjuvant (particularly a mucosal adjuvant), needs to be tested for its efficiency as [a] mucosal adjuvant even when it is able to interact with macrophages and/or DCs, because[, inter alia,] . . . an activator of macrophages and/or DCs cannot be considered a priori an adjuvant (or, more particularly, a mucosal adjuvant). (Guzman Decl. ¶ 5; see also Mühlradt Decl.11 ¶ 4 (Mühlradt declares “that a macrophage stimulator such as MALP-2 is not a priori an adjuvant, and in particular, is not necessarily a mucosal adjuvant”); Mühlradt Decl. ¶ 6 (Mühlradt declares that “one of ordinary skill in the art would know that the effectiveness of a known adjuvant in a new experimental setting cannot be foreseen”).) FF 16. Guzman distinguishes the CT protein, addressed in Foss, from the MALP-2 peptide set forth in Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97 (Guzman ¶ 5). ANALYSIS Based on Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97 in combination with Foss, Examiner concludes that, at the time Appellants’ invention was made, it would have been prima facie obvious to utilize a peptide within the scope of Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97 as a mucosal adjuvant (see Ans. 3–5). We are not persuaded. The consistent criterion for determination of obviousness is whether the prior art would have suggested to one of ordinary skill in the art that this process should be carried out and would have a reasonable likelihood of success, viewed in the light of the prior art . . . . Both the suggestion and the expectation of 11 Declaration of Peter F. Mühlradt, signed May 10, 2009. Appeal 2018-005471 Application 13/848,936 9 success must be founded in the prior art, not in the applicant’s disclosure. In re Dow Chemical Co., 837 F.2d 469, 473 (Fed. Cir. 1988) (citations omitted). Although Examiner finds, on this record, that a person of ordinary skill in this art would “have had a reasonable expectation of success” using MALP-2 peptides, such as those disclosed by Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97 “as a mucosal adjuvant,” because “mucosal adjuvants function by activating macrophages and [the peptides disclosed by Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97] . . . are disclosed to activate macrophages,” the evidence of record establishes “that a macrophage stimulator such as MALP-2 is not a priori an adjuvant, and in particular, is not necessarily a mucosal adjuvant” (see Ans. 3–5; cf. FF 15; App. Br.12 20 (“One of skill in the art would recognize that adjuvants in general are not necessarily useful for mucosal administration”); see generally Reply Br. 2 (“one of ordinary skill in the art would not have had a reasonable expectation of success from the proposed combination of Mühlradt and Foss”)). To the contrary, Foss discloses that there is “a wide variety of potential mechanisms for adjuvants to enhance mucosal immunity” and that the “[d]elivery of protein antigens to the GALT can result in immunity or oral tolerance depending on the circumstances of the encounter” (FF 7–8; see App. Br. 25 (“Foss does not provide a unifying theory that could be used to predict whether or not a substance could be successfully used as an adjuvant, let alone whether it would be successful for a particular route of administration, for a particular antigen”)). In this regard, the evidence of record establishes that “there are no overall macrophage-driven mechanisms 12 Appellants’ November 8, 2017 Appeal Brief. Appeal 2018-005471 Application 13/848,936 10 responsible for mucosal adjuvancity, that specific interactions with macrophages could be dispensable and that several distinct mechanisms can be in part leading to mucosal adjuvanticity” (FF 13). Thus, taken as a whole, the evidence of record establishes that there “is not a reasonable expectation that molecules which are able to activate macrophages are generally acting as mucosal adjuvants” (FF 14). Thus, although we agree with Examiner that, at the time of Appellants’ claimed invention, the prior art provided a general approach that seemed to be a promising field of experimentation (see FF 1–10), the prior art, on this record, gave only general guidance relating to one, of several, possible mechanisms for achieving mucosal immunity, with an adjuvant that differs from Appellants’ claimed peptide (see generally FF 16; App. Br. 22 (“There is no reason to assume that results obtained with protein adjuvants such as CT . . . , especially given the inconsistent adjuvanticity of CT, would be indicative of results that could be expected with MALPS”); Reply Br. 2 (“Foss relates to cholera toxin, a large molecule, while MALP2 represents a small molecule comparable to other small molecule adjuvants not suitable for mucosal administration”)). As Appellants explain: No common chemical structure, mechanism of action, or other properties that could predict adjuvanticity with surety, especially mucosal adjuvanticity, are taught by Foss, that could have been reliably used by one of skill in the art to predict, with a reasonable expectation of success, that the lipopeptides/lipoproteins taught by Mühlradt would be efficacious as mucosal antigens. (App. Br. 26 (emphasis omitted).) To the contrary, the evidence on this record supports a conclusion that every compound, before it can be determined to be an adjuvant (particularly a mucosal adjuvant), needs to be tested for its Appeal 2018-005471 Application 13/848,936 11 efficiency as [a] mucosal adjuvant even when it is able to interact with macrophages and/or DCs, because[, inter alia,] . . . an activator of macrophages and/or DCs cannot be considered a priori an adjuvant (or, more particularly, a mucosal adjuvant). (FF 15; see also App. Br. 20 (“to establish efficacy as a mucosal adjuvant, a substance must be tested in one or more art recognized systems”)). [A]n invention is not obvious to try where vague prior art does not guide an inventor toward a particular solution. A finding of obviousness would not obtain where “what was ‘obvious to try’ was to explore a new technology or general approach that seemed to be a promising field of experimentation, where the prior art gave only general guidance as to the particular form of the claimed invention or how to achieve it.” . . . This expresses the same idea as the KSR requirement that the identified solutions be “predictable.” Bayer Schering Pharma AG v. Barr Laboratories, Inc., 575 F.3d 1341, 1347 (Fed. Cir. 2009) (citations omitted). For the foregoing reasons, Examiner has, at best, established that it would have been obvious to try the methodology set forth in the combination of Mühlradt ’242, Mühlradt ’110, or Mühlradt ’97, with Foss in order to arrive at Appellants’ claimed invention. “‘[O]bvious to try[,’ however,] is not the standard under § 103.” In re O’Farrell, 853 F.2d 894, 903 (Fed. Cir. 1988). CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness. The rejection of claims 12–22 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’242 and Foss is reversed. The rejection of claims 12–22 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’110 and Foss is reversed. Appeal 2018-005471 Application 13/848,936 12 The rejection of claims 12–22 under 35 U.S.C. § 103(a) as unpatentable over the combination of Mühlradt ’97 and Foss is reversed. Obviousness-type Double Patenting: ISSUE Does the preponderance of evidence relied upon by Examiner support a conclusion of obviousness-type double patenting? ANALYSIS Examiner finds that although “the adjuvant compositions are the same in both [Mühlradt ’242] . . . and [Appellants’] claims, the [Mühlradt ’242] . . . claims differ from [Appellants’ claimed invention] . . . in that they do not explicitly disclose the mucosal administration of the adjuvant composition” (Ans. 2). Examiner reasons, however, given that the [Mühlradt ’242] . . . composition is a macrophage activator . . . and Foss . . . disclose[s] that mucosal adjuvants function by activating macrophages . . . , it would have been [prima facie] obvious[, at the time of Appellants’ claimed invention,] for one of ordinary skill in the art to use the composition of [Mühlradt ’242] . . . as a mucosal adjuvant. (Id.) We are not persuaded. As Appellants explain, for the reasons discussed in their response to Examiner’s obviousness rejections, “Foss does not teach that substances as described by [Mühlradt ’242] should or could successfully be used as mucosal adjuvants” and the evidence of record, as discussed above with respect to the obviousness rejection, establishes that this “art is unpredictable” (see App. Br. 29). We agree. Thus, for the reasons set forth above, with respect to the obviousness rejections on this record, we find that Examiner failed to establish an Appeal 2018-005471 Application 13/848,936 13 evidentiary basis to support the obviousness-type double patenting rejection on this record. CONCLUSION The preponderance of evidence relied upon by Examiner fails to support a conclusion of obviousness-type double patenting. The rejection of claims 12, 13, 15, 16, 20, and 22 under the judicially created doctrine of obviousness-type double patenting as being unpatentable over the claims of Mühlradt ’242 and Foss is reversed. REVERSED Copy with citationCopy as parenthetical citation