Ex Parte Farokhzad et alDownload PDFPatent Trial and Appeal BoardMay 3, 201812515465 (P.T.A.B. May. 3, 2018) Copy Citation UNITED STA TES p A TENT AND TRADEMARK OFFICE APPLICATION NO. FILING DATE 12/515,465 05/05/2010 23579 7590 05/04/2018 Pabst Patent Group LLP 1545 PEACHTREE STREET NE SUITE 320 ATLANTA, GA 30309 FIRST NAMED INVENTOR Omid C. Farokhzad 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. MIT 12477 9774 EXAMINER DAHLE, CHUN WU ART UNIT PAPER NUMBER 1644 MAIL DATE DELIVERY MODE 05/04/2018 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 OMID C. F AROKHZAD, FRANK ALEXIS, TIMOTHY T. KUO, ERIC PRIDGEN, ALEKSANDAR FILIP RADOVIC-MORENO, and ROBERTS. LANGER1 Appeal2017-001466 Application 12/515,465 Technology Center 1600 Before DONALD E. ADAMS, ERIC B. GRIMES, and RYAN H. FLAX, Administrative Patent Judges. GRIMES, Administrative Patent Judge. DECISION ON APPEAL This is an appeal under 35 U.S.C. § 134 involving claims to nanoparticles for delivery of an active agent, which have been rejected as lacking adequate written description, nonenabled, and obvious. We have jurisdiction under 35 U.S.C. § 6(b ). We reverse both rejections under 35 U.S.C. § 112, first paragraph, but affirm the rejections for obviousness. 1 Appellants identify the Real Parties in Interest as Massachusetts Institute of Technology; The Brigham and Women's Hospital, Inc.; and Bind Biosciences, Inc. (Appeal Br. 3.) Appeal2017-001466 Application 12/515,465 STATEMENT OF THE CASE "The FcRn receptor molecule is well characterized. The FcRn receptor binds IgG (but not other immunoglobulin classes such as IgA, IgD, IgM, and/or IgE) at acidic pH and not at basic pH. FcRn transports IgG across epithelial cells." Spec. ,r 5. "FcRn binding partners include whole IgG, the F c fragment of IgG, and/ or other fragments of IgG that include the complete binding region for the FcRn receptor." Id. "The present invention relates to F cRn binding partners for the targeted delivery of vaccines, antigens, drugs, therapeutics, microparticles, nanoparticles, picoparticles, etc. to and/or across epithelial and/or endothelial barriers." Id. "By using FcRn targeted nanoparticles, it may be possible to enhance delivery across cells, layers of cells, and/or tissues, resulting in improved drug distribution and targeting." Id. Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117 are on appeal. Claim 1 is illustrative and reads as follows: 1. A polymeric nanoparticle having a size in the range of 10 to 500 nm, compnsmg an F cRn binding partner comprising an IgG F c fragment at least 80% homologous to SEQ ID No.: 1, wherein the Fe fragment includes a complete binding region to an FcRn receptor, and wherein the binding partner is present on the surface of the nanoparticle and binds to an FcRn receptor to cause transcytosis of the nanoparticle through a cell layer, and a therapeutic, diagnostic, prognostic, or prophylactic agent for delivery into an interstitial space of endothelium. The claims stand rejected as follows: Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117 under 35 U.S.C. § 112, first paragraph, as lacking adequate written description (Ans. 6); 2 Appeal2017-001466 Application 12/515,465 Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, 114, 115, and 117 under 35 U.S.C. § 112, first paragraph, as nonenabled (Ans. 2); Claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, and 78 under 35 U.S.C. § 103 (a) as obvious based on Blumberg,2 Presta, 3 Maruyama, 4 and either Farokhzad5 or Cheng6 (Ans. 9); Claims 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, and 114 under 35 U.S.C. § I03(a) as obvious based on Blumberg, Presta, Maruyama, either Farokhzad or Cheng, and Harris 7 (Ans. 12-13); Claims 1, 115, and 117 under 35 U.S.C. § I03(a) as obvious based on Blumberg, Presta, Maruyama, either Farokhzad or Cheng, Harris, and Ruoslahti8 (Ans. 13-14). I The Examiner has rejected all of the claims on appeal for lack of adequate written description and nonenablement. The Examiner relies on 2 Blumberg et al., US 6,060,613, issued Feb. 29, 2000. 3 Presta, US 6,737,056 Bl, issued May 18, 2004. 4 Maruyama et al., Tragetability of novel immunoliposomes modified with amphipathic poly(ethylene glycol)s conjugated at their distal terminals to monoclonal antibodies, 1234 BIOCHIMICA ET BIOPHYSICA ACTA 74--80 (1995). 5 Farokhzad et al., Nanoparticle-Aptamer Bioconjugates: A New Approach for Targeting Prostate Cancer Cells, 64 CANCER RESEARCH 7668-7672 (2004). 6 Cheng et al., Formulation of Functional PLGA-PEG Nanoparticlesfor in vivo targeted drug delivery, 28 BIOMATERIALS 869-876 (2007). 7 Harris et al., Proteolytic Actuation of Nanoparticle Self-Assembly, 118 ANGEW. CHEM. 3233-3237 (2006). 8 Ruoslahti et al., US 7,488,792 B2, issued Feb. 10, 2009. 3 Appeal2017-001466 Application 12/515,465 similar fact-finding and reasoning for both rejections. We will therefore address them together. Regarding the written description requirement, the Examiner finds that"[ w ]ith respect to the FcRn binding partner, the only disclosure in the specification appears to be IgG antibodies having the Fe region." Ans. 6. Similarly, regarding enablement, the Examiner finds that, "[ w ]ith respect to the F cRn binding partner comprising IgG F c fragment at least 80% homologous to SEQ ID NO: 1, the only disclosure in the specification appears to be antibodies having the full length IgG Fe region." Ans. 3. With regard to both rejections, the Examiner finds that "there is insufficient guidance and directions regarding how to modify the Fe region for an Fe fragment including a fragment that is at least 80% identical to human IgG Fe region including SEQ ID NO: 1 or how to use whole antibodies with different antigen specificities while maintaining the functions, e.g. binding to FcRn." Id. at 3, 6. The Examiner finds that the prior art shows that "even single amino acid differences can result in drastically altered binding affinity of the Fe region of antibodies to FcRn." Id. at 4, citing Martin. 9 The Examiner also finds that determinants of antibody properties, including solubility and affinity, are overlapping, so that "engineering an antibody to be more soluble may cause a loss in affinity for its antigen." Id., citing Lazar. 1° Finally, the 9 Martin et al., Crystal Structure at 2.8 A of an FcRn/Heterodimeric Fe Complex: Mechanism of pH-Dependent Binding, 7 MOLECULAR CELL 867- 877 (2001). 10 Lazar et al., WO 03/074679 A2, Sept. 12, 2003. 4 Appeal2017-001466 Application 12/515,465 Examiner finds that "a large number of residues were found that affected binding ofigGl to human FcRn." Id., citing Shields. 11 The Examiner repeats these findings in rejecting the claims for lack of adequate descriptive support. Id. at 8. The Examiner concludes that it is not clear that the in vitro results described in the Specification, using the full-length Fe region of human IgG, "would be sufficient to enable the entire genus" of the claims, id., and that "the experimentation left to those skilled in the art, is unnecessarily, and improperly, extensive and undue." Id. at 6. The Examiner also concludes that "it does not appear based upon the limited disclosure of full length Fe region of IgG alone and specific agent ( e.g. CREKA) alone that appellant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus." Id. at 8-9. With respect to written description, Appellants argue that "claim 1 is not drawn to genera of FcRn binding partners lacking any common structure, as alleged by the Examiner. In contrast, the structural features required to perform the claimed function of binding to the FcRn are explicitly defined." Appeal Br. 13. More specifically, "the points of contact between the component of the Fe portion ofigG that bind to the FcRn receptor, as determined by X-ray crystallography, are explicitly recited in the specification (see paragraph [0005] ... )." Id. at 14. Appellants also argue that "the crystal structure and description of the contacts between the 11 Shields et al., High Resolution Mapping of the Binding Site on Human IgG 1 for Fey RI, FcyRIL FcyRIIL and FcRn and design of IgG 1 Variants with Improved binding to the FcyR, 276 J. BIOL. CHEM. 6591-6604 (2001). 5 Appeal2017-001466 Application 12/515,465 Fe portion of IgG and the FcRn receptor were published in 1994." Id., citing Burmeister. 12 Appellants conclude that "one of skill in the art would recognize the Appellants were in possession of the necessary common attributes or features of the elements possessed by the claimed nanoparticles." Id. at 20. With respect to enablement, Appellants argue that "the specification recognizes that certain positions in the Fe region can be modified and states that positions remote from the FcRn contact sites as well as modifications within the FcRn contact sites can be modified to preserve or enhance the Fc- FcRn interactions, as set forth in paragraph [0005]" of the Specification. Appeal Br. 27. Appellants also argue that "methods to modify proteins and peptides through addition, deletion, mutation or otherwise altering one or more amino acids within a protein were routine" in the art as of this application's filing date. Id. Appellants conclude that a person of ordinary skill in the art could make and use the claimed nanoparticles "based on the guidance set forth in the specification as filed, and the level of ordinary skill in the art at the time of filing." Id. at 31. We agree with Appellants that, based on the Specification's disclosure and the knowledge existing in the art at the time this application was filed, a person of ordinary skill in the art would not have needed to carry out undue experimentation to practice the claimed invention and would have recognized that Appellants were in possession of the claimed invention based on the Specification's description of it. 12 Burmeister et al., Crystal structure of the complex of rat neonatal Fe receptor with Fe, 372 NATURE 379--383 (1994). 6 Appeal2017-001466 Application 12/515,465 "Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations." In re Wands, 858 F.2d 731, 737 (Fed. Cir. 1988). Among those considerations are the state of the prior art, the relative skill of those in the art, and the predictability or unpredictability of the art. Id. "The specification need not explicitly teach those in the art to make and use the invention; the requirement is satisfied if, given what they already know, the specification teaches those in the art enough that they can make and use the invention without 'undue experimentation."' Amgen, Inc. v. Hoechst Marion Roussel, Inc., 314 F.3d 1313, 1334 (Fed. Cir. 2003). A "sufficient description of a genus ... requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can 'visualize or recognize' the members of the genus." Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010) (en bane). However, "[t]he 'written description' requirement must be applied in the context of the particular invention and the state of the knowledge." Capon v. Eshhar, 418 F.3d 1349, 1358 (Fed. Cir. 2005). "[T]he determination of what is needed to support generic claims to biological subject matter depends on a variety of factors, such as the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, the predictability of the aspect at issue, and other considerations appropriate to the subject matter." Id. at 1359. 7 Appeal2017-001466 Application 12/515,465 Here, the evidence of record shows that the relevant amino acid residues in the Fe fragment of IgG were well-known at the time the instant application was filed. The Specification states that [t]he region of the Fe portion of IgG that binds to the FcRn receptor has been described based upon X-ray crystallography (Burmeister, et al., 1994, Nature, 372:379; incorporated herein by reference). The major contact area of Fe with the FcRn receptor is near the junction of the CH2 and CH3 domains. Potential contacts are residues 248, 250-257, 272, 285, 288, 290-291, 308-311, and/or 314 in CH2 and 385-387, 428, and/or 433-436 in CH3. Spec. ,r 5. The Specification's statements are supported by Burmeister. See Burmeister 379, right col. and 383, Table 2(a). In addition, the Martin and Shields references cited by the Examiner show that numerous amino acid changes in the Fe domain of IgG had previously been made, and disclose the effect of those changes on Fc/FcRn interactions. Martin, for example, discloses mutations in the human IgG 1 Fe domain that either reduced or enhanced binding to human FcRn. Martin 874, Table 4. "From these results and an analysis of the FcRn/hdFc [heterodimeric version of F c] structure, [Martin] suggest[ s] a general strategy for identification of Fe mutants with increased affinity for FcRn." Id. at 873-874. Shields discloses "a complete, high resolution mapping of human IgG 1 ... for human FcRn." Shields 6592, left col. "The binding site on human IgG 1 for the various receptors was determined by individually changing all solvent-exposed amino acids in human IgG 1 CH2 and CH3 domains ... to Ala." Id. Shields discloses the "[b ]inding of human IgG 1 variants to human FcRn." Id. at 6595, Table I. Among the variants are 8 Appeal2017-001466 Application 12/515,465 those in Class 10, which "affect only FcRn." Id. Some of the Class 10 variants showed reduced binding and some showed improved binding, compared to native IgG 1. Id.; see also id. at footnote b. The Examiner also cites Lazar's disclosure that "the determinants of antibody stability, solubility, and affinity for antigen are overlapping and the interactions that contribute to these properties are related. Thus, affinity maturation of an antibody may result in decreased stability, and optimization of an antibody's solubility may cause a loss in affinity for its antigen." Lazar 3:21-24; see also Ans. 4, 8. However, this teaching is of limited relevance to the claimed invention, which is based on the interaction of the Fe domain ofigGl with the FcRn receptor, not on the antigenic specificity of any given antibody. Thus, the evidence shows that those skilled in the art were aware of what portions of the Fe domain were responsible for FcRn interaction (Spec. ,r 5, Burmeister), and were aware of the effects of various amino acid substitutions on the Fc/FcRn interaction (Martin, Shields). The evidence also shows that Martin had suggested, before the instant application's filing date, "a general strategy for identification of Fe mutants with increased affinity for FcRn." Martin 873-74. In view of the existing knowledge in the art, the high level of skill in the art, and the routine nature of making and testing substitution mutations in the IgG Fe domain, as evidenced by Martin and Shields, we conclude that the Examiner has not shown by a preponderance of the evidence that undue experimentation would be required to make and use the claimed nanoparticles. Similarly, in view of the "the existing knowledge in the 9 Appeal2017-001466 Application 12/515,465 particular field, the extent and content of the prior art, [and] the maturity of the science or technology" Capon, 418 F.3d at 1359, the Examiner has not shown by a preponderance of the evidence that those skilled in the art would not have recognized from the Specification's description that Appellants were in possession of the claimed genus of nanoparticles. In summary, we reverse both of the rejections under 35 U.S.C. § 112, first paragraph. II The Examiner has rejected claims 1, 15, 20, 27, 32, 36, 38, 39, 75, 76, and 78 under 35 U.S.C. § 103(a) as obvious based on Blumberg, Presta, Maruyama, and either Farokhzad or Cheng. The Examiner finds that Blumberg discloses "delivery of a therapeutic drug or an antigen by administering to the luminal side of an epithelial barrier of an epithelial tissue expressing an FcRn receptor a conjugate of an FcR[n] binding partner and a drug or antigen." Ans. 9. The "binding partner can be Fe fragment of the human IgG." Id. "[T]he FcRn mediated transport system can be used for the delivery of a wide variety of compounds including chemotherapeutic agent[s]." Id. at 10. The Examiner finds that Presta discloses the amino acid sequence of the human IgG 1 Fe region. Id. The Examiner cites Appellants' Specification as evidence that the amino acid sequence of SEQ ID NO: 1, recited in claim 1, is from human IgG 1. Id. The Examiner finds that Maruyama discloses liposomes modified with polyethylene glycol (PEG) molecules having antibodies attached at their distal termini. Id. The Examiner also finds that Maruyama suggests 10 Appeal2017-001466 Application 12/515,465 using the resulting immunoliposomes for targeted drug delivery because they should provide high local concentrations of an encapsulated drug at a target site. Id. at 10-11. The Examiner finds that both Farokhzad and Cheng teach polymeric nanoparticles, which included PEG as part of the polymer, conjugated to aptamers. Id. at 11-12. The Examiner finds that Farokhzad suggests using the nanoparticle conjugates for targeted delivery of chemotherapeutic drugs and Cheng suggests using conjugates that include an aptamer that binds to prostate specific membrane antigen (PMSA) for targeted tumor-specific drug delivery. Id. The Examiner concludes that it would have been obvious to use the IgG 1 Fe delivery system taught by Blumberg to deliver the nanoparticles of Farokhzad or Cheng with the antibody attached to their surface via PEG, as taught by Maruyama, to deliver chemotherapeutic agents, as suggested by both Farokhzad or Cheng. Id. at 12. We agree with the Examiner that the nanoparticles of claim 1 would have been obvious to a person of ordinary skill in the art based on the cited references. Blumberg discloses that "antigens may be coupled to molecules that bind to the FcRn receptor, such as immunoglobulins, or portions thereof, and delivered across epithelial barriers ... via FcRn receptors." Blumberg 3 :36-40. The most preferred FcRn binding partner is an Fe fragment of IgG. Id. at 4:2--4. "[T]he FcRn binding partner may be produced by recombinant genetic engineering techniques. Within the scope of the invention are nucleotide sequences encoding human FcRn binding partners." Id. at 6:65 to 7:2. 11 Appeal2017-001466 Application 12/515,465 Blumberg states that "[t]he FcRn receptor binds IgG (but not other immunoglobulin classes such as IgA, IgD, IgM and IgE) at a relatively lower pH, actively transports the IgG transcellularly in a luminal to serosal direction, and then releases the IgG at a relatively higher pH found in the interstitial fluids." Id. at 6:31-36. Blumberg states that its conjugates are therefore "useful whenever it is desirable to achieve systemic delivery of a therapeutic or drug or delivery vehicle across an epithelial barrier to systemic circulation," and "may be used to deliver therapeutics across intestinal epithelial tissue, lung epithelial tissue, and other mucosal epithelial surfaces." Id. at 5:43--48. Blumberg also teaches that "FcRn binding partners ... may be utilized for the delivery of a wide variety of compounds and therapeutics and bioactive substances, including but not limited to, chemotherapy agents for the treatment of cancer," etc. Id. at 3 :58---61. Blumberg teaches that its conjugates can include "a variety of therapeutics or drugs for targeted systemic delivery." Id. at 11:66---67; see also id. at 12:22 to 13:62 (listing exemplary drugs that can be used). "The FcRn binding partners of the present invention may further be utilized for the targeted delivery of a delivery vehicle, such as liposomes." Id. at 3:64---67. Presta discloses the amino acid sequence of the human IgG 1 F c region. Presta 9:18-20 and Fig. 22A. Appellants' Specification provides evidence that SEQ ID NO: 1, recited in claim 1, is "the sequence of the Fe portion of a human IgG 1 antibody." Spec. ,r 54. Maruyama discloses that DSPE-PEG-COOH (distearoyl-N-(3- carboxypropionoyl poly( ethylene glycol) succinyl)phosphatidylethanolamine) 12 Appeal2017-001466 Application 12/515,465 was "used to prepare novel immunoliposomes carrying monoclonal antibodies at the distal ends of the PEG chains (Type C)." Maruyama 74, abstract. Maruyama's Figure 1 is reproduced below: Type A Type a Type C Figure 1 shows "immobilization of antibody on liposomes. . . . Type C: new type of PEG-immunoliposomes with antibody attached to the distal terminal of DSPE-PEG-COOH." Id. at 75, legend to Figure 1. Maruyama states that "conjugation of antibody directly to the PEG terminal provides excellent target binding and retention of immunoliposomes." Id. at 80, left col. Maruyama also states that "Type C liposomes have great potential as a targeted drug delivery vehicle. They should be able to provide a high local concentration of the encapsulated drug at the target site for a prolonged period of time." Id. Farokhzad discloses nanoparticles "synthesized [from] poly(lactic acid)-block-polyethylene glycol (PEG) copolymer with a terminal carboxylic acid functional group (PLA-PEG-COOH)." Farokhzad 7668, abstract. The nanoparticles have "carboxylic acid groups on the particle surface for potential modification and covalent conjugation to amine-modified aptamers." Id. Farokhzad "generated nanoparticle-aptamer bioconjugates with RNA aptamers that bind to the prostate-specific membrane antigen, a well-known prostate cancer tumor marker." Id. The PLA-PEG-COOH nanoparticles had a mean size of 249 ± 12 nm. Id. at 7669, Fig. 1. Farokhzad states that its 13 Appeal2017-001466 Application 12/515,465 "nanoparticle-aptamer bioconjugates, which target and are taken up by prostate cancer epithelial cells[,] ... are potentially suitable for efficient and specific targeted delivery of chemotherapeutic drugs to prostate cancer cells." Id. at 7671, left col. Cheng also discloses polymeric nanoparticles (NPs) conjugated to an aptamer (Al 0) that targets prostate-specific membrane antigen (PMSA), but its nanoparticles were made from a different polymer (PLGA-b-PEG-COOH) than Farokhzad's nanoparticles. Cheng 869, abstract. "The surface functionalization ofNPs with the AIO PSMA Apt significantly enhanced delivery ofNPs to tumors." Id. "Cheng states that its nanoparticles provide "tumor specific systemic targeting of a NP-Apt bioconjugate system in vivo and may result in the development of therapeutically effective vehicles for disseminated prostate cancer." Id. at 875, left col. Based on the cited references, the nanoparticles of claim 1 would have been obvious to a person of ordinary skill in the art. Blumberg teaches that a therapeutic agent that is conjugated to an FcRn binding partner, such as an Fe fragment of human IgG, will be transported from the surface of epithelial tissue into the interstitial fluid and into the systemic circulation. Presta teaches the FcRn binding region of human IgGl (SEQ ID NO: 1). Thus, it would have been obvious to use the FcRn binding region of the Fe fragment of human IgG 1 as the FcRn binding partner in Blumberg's conjugates with a therapeutic agent. Although Blumberg does not disclose using its conjugates to deliver nanoparticles containing a therapeutic agent, it does disclose that F cRn binding partners can be used for targeted delivery to the systemic circulation 14 Appeal2017-001466 Application 12/515,465 of delivery vehicles, such as liposomes. Both Farokhzad and Cheng disclose that polymeric nanoparticles having PEG moieties on the surface can be conjugated to a binding partner, such as an RNA aptamer, in order to deliver a drug to particular cells. Thus, it would have been obvious to modify Blumberg's FcRn-targeted liposomes by substituting the polymeric nanoparticles taught by Farokhzad and Cheng for Blumberg's liposomes. See KSR Int'! Co. v. Teleflex Inc., 550 U.S. 398,416 (2007) ("[W]hen a patent claims a structure already known in the prior art that is altered by the mere substitution of one element for another known in the field, the combination must do more than yield a predictable result." (discussing United States v. Adams, 383 U.S. 39, 50-51 (1966))). Both Farokhzad and Cheng disclose that target-specific aptamers are conjugated to the polymeric nanoparticles via PEG moieties on the surface of the nanoparticles. Maruyama similarly teaches that antibodies can be conjugated to PEG moieties on the surface of liposomes in order to target a drug to a target site. Based on these teachings, it would have been obvious to attach the FcRn-binding IgG 1 Fe fragment suggested by Blumberg and Presta to the PEG moieties on the surface of the polymeric nanoparticles of Farokhzad or Cheng, in order to target the nanoparticles to the FcRn receptor, as taught by Blumberg. In summary, the cited references disclose all of the limitations of claim 1 and provide a reason to combine the elements of the claimed nanoparticles in the manner recited in the claim. Claim 1 therefore would have been prima facie obvious to a person of ordinary skill in the art, based on the cited references. 15 Appeal2017-001466 Application 12/515,465 Appellants argue that "Cheng represents the inventor's own work and is not available as effective prior art to the claimed subject matter." Appeal Br. 39, citing the Farokhzad Declaration. 13 We conclude that the Farokhzad Declaration is sufficient to show that Cheng does not represent a disclosure "by others," 35 U.S.C. § 102(a), and therefore does not qualify as prior art with respect to the claimed invention. The Examiner concludes that "[t]he Farokhzad declaration is insufficient to demonstrate that Cheng et al. is appellants' own work," Ans. 25, but cites no evidence that contradicts the declaration's statement that the authors of Cheng who are not inventors of the instant application "did not contribute to the conception or reduction to practice of the [ claimed] functionalized nanoparticles for targeted drug delivery." Farokhzad Deel. ,r 3. "[ A ]uthorship of an article by itself does not raise a presumption of inventorship with respect to the subject matter disclosed in the article. Thus, co-authors may not be presumed to be coinventors merely from the fact of co-authorship." In re Katz, 687 F.2d 450, 455 (CCPA 1982). Here, the inventors have declared that the authors of Cheng who are not named as inventors of the instant application did not make an inventive contribution to the claimed products. Given the absence of evidence to the contrary, we 13 Declaration of all of the inventors, filed June 30, 2015. Although the Declaration states that it was filed under 3 7 C.F .R. § 1.131, the purpose of the declaration is to show that the non-inventor authors of Cheng "did not contribute to the conception or reduction to practice of the [ claimed] functionalized nanoparticles for targeted drug delivery." Farokhzad Deel. ,r 3. We therefore have treated the declaration as having been filed under 37 C.F.R. § 1.132. See In re Katz, 687 F.2d450 (CCPA 1982). 16 Appeal2017-001466 Application 12/515,465 accept the declaration's statement as accurate. Therefore, Cheng does not qualify as prior art with respect to the claims on appeal. We conclude that the remaining references support a prima facie case of obviousness, however, because the relevant teachings of Cheng are also provided by Farokhzad. Thus, Blumberg, Presta, Maruyama, and Farokhzad support a prima facie case of obviousness with respect to claim 1. Appellants also argue that none of Blumberg, Presta or Maruyama disclose or suggest nanoparticles, and Farokhzad does not disclose FcRn binding partners. Appeal Br. 41--43. "Non-obviousness cannot be established by attacking references individually where the rejection is based upon the teachings of a combination of references." In re Merck & Co., 800 F.2d 1091, 1097 (Fed. Cir. 1986). "The test for obviousness is what the combined teachings of the references would have suggested to one of ordinary skill in the art." In re Young, 927 F.2d 588, 591 (Fed. Cir. 1991). Here, for the reasons discussed above, we conclude that the combined teachings of Blumberg, Presta, Maruyama, and Farokhzad would have made obvious the nanoparticles defined by claim 1. Appellants argue that "none of the cited art could lead the skilled person to combine Presta, Farokhzad or Maruyama with Blumberg, because none of these references suggest that polymeric nanoparticles including active agents can exploit surface-bound Fe to initiate FcRn-mediated transcytosis of a nanoparticle of greater than 10 nm in size." Appeal Br. 46. Appellants argue that "[i]t was not known prior to Appellant's filing date that polymeric nanoparticles (i.e., 10-500 nm in size) could exploit the FcRn-mediated trans-cellular pathway mechanism to achieve the targeted 17 Appeal2017-001466 Application 12/515,465 delivery of therapeutic, diagnostic or prognostic agents to the interstitial space." Id. at 43. Appellants argue that "[t]he use of an Fc/FcRn interaction to mediate internalization and transcytosis of a nanoparticle delivery vehicle represents an unexpected and surprising result in view of the cited art, at least because of the unique pH-dependence of the FcRn interactions." Id. These arguments are unpersuasive. Farokhzad states that its "nanoparticle-aptamer bioconjugates ... are taken up by prostate cancer epithelial cells." Farokhzad 7 671, left col. ( emphasis added). A person of ordinary skill in the art would therefore expect that nanoparticles 249 nm in size (like those ofFarokhzad) would be taken up by-i.e., internalized or endocytosed-by target cells to which they bind. Appellants have pointed to no evidence showing that cells expressing the F cRn receptor differ in their endocytosis characteristics from the prostate cancer epithelial tissues targeted by Farokhzad's bioconjugates. In addition, the pH-dependence of FcRn/IgG interactions was well known in the art. See Blumberg 2:9-20 ("[T]he Fe portion of IgG is bound to the enterocyte receptor at the relatively acidic pH of the lumen ( about pH 6.0). Following transcytosis to the basolateral plasma membrane, discharge of the immunoglobulin occurs at the relatively neutral pH of the interstitial fluids (about pH 7.4)."). Thus, the cited references support the Examiner's conclusion that a person of ordinary skill in the art would have had a reason to combine their respective teachings with a reasonable expectation of success. The evidence does not support Appellants' argument that the claimed nanoparticles provide surprising or unexpected results. 18 Appeal2017-001466 Application 12/515,465 Appellants argue that "nothing in the cited art teaches or suggests the specific interaction of the claimed nanoparticles with endothelial or epithelial cells defined by claim 15." Appeal Br. 47--48. However, Blumberg expressly states that its conjugates can be used "to achieve systemic delivery of a therapeutic or drug or delivery vehicle across an epithelial barrier to systemic circulation," and "may be used to deliver therapeutics across intestinal epithelial tissue, lung epithelial tissue, and other mucosal epithelial surfaces." Blumberg 5:43--48. The cited references therefore would have made obvious nanoparticles that are able to bind to the F cRn receptor of epithelial cells, as recited in claim 15. With respect to claims 36, 39, 75, 76, and 78, Appellants argue that, "[a]s discussed, nothing in the combination of art describes or suggests polymeric nanoparticles including surface-bound FcRn binding partners, irrespective of the type of association between the particle and the FcRn binding partner, and/or therapeutic, diagnostic, prognostic, or prophylactic agent." Appeal Br. 48. This argument is unpersuasive for the reasons discussed above. With respect to claims 20 and 27, Appellants argue that, "nothing in the combination of the cited art teaches or suggests polymeric nanoparticles including FcRn binding partners can be useful for the delivery of therapeutics to interstitial spaces through FcRn-mediated transcytosis across an endothelial cell layer." Appeal Br. 49. This argument is unpersuasive. Blumberg discloses that its conjugates can be used to deliver a variety of drugs to the systemic circulation by oral or pulmonary administration (i.e., inhalation), as recited in claim 27. See 19 Appeal2017-001466 Application 12/515,465 Blumberg 16:53-56. Blumberg also discloses that its conjugates can be used to deliver, among other things, a thrombolytic agent (tissue plasminogen activator), as recited in claim 20. Id. at 13:30-31. Thus, the cited references would have made obvious the nanoparticles of claims 20 and 27. With regard to claim 32, Appellants argue that "no art has been cited to lead one skilled in the art to believe liposomes are equivalent in structure or function, or can be targeted in the same way." Appeal Br. 49-50. Claim 32 recites specific polymers for the claimed polymeric nanoparticles, including polylactic acid and polyethylene glycol. Farokhzad discloses nanoparticles made from poly(lactic acid)-block-polyethylene glycol copolymer. Farokhzad 7668, abstract. For the reasons discussed above, therefore, the cited references therefore would have made obvious the nanoparticles defined by claim 32. With respect to claim 38, Appellants argue that Blumberg "is drawn to a single Fe or IgG conjugated to antigen. Nothing in the combination of Blumberg and the other cited art references teaches or suggests polymeric particles, least of all nanoparticles having a multiplicity of FcRn binding partners associated with their surface." Appeal Br. 50. This argument is unpersuasive. For the reasons discussed above, the cited references would have made obvious the combination of Blumberg' s FcRn binding partners and Farokhzad's polymeric nanoparticles and, given their relative sizes, a skilled artisan would have reasonably expected that the nanoparticles would have multiple FcRn binding partners associated with their surfaces. In addition, Farokhzad discloses that its nanoparticles have 20 Appeal2017-001466 Application 12/515,465 carboxylic acid "groups" (plural) on their surfaces for conjugation to "aptamers" (plural). Farokhzad 7668, abstract. Thus, the cited references would have made obvious the nanoparticles defined by claim 38. IV The Examiner has rejected claims 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, and 114 as obvious based on Blumberg, Presta, Maruyama, either Farokhzad or Cheng, and Harris. With regard to claims 112 and 114, Appellants argue that "Harris does not make up for the deficiencies of Blumberg, Presta, Farokhzad, Maruyama and Cheng, at least because Harris does not teach or suggest polymeric nanoparticles, or FcRn binding partners having at least 80% homology to SEQ ID NO.: 1, least of all nanoparticles having a multiplicity of such molecules at the surface of the particle." Appeal Br. 51. Appellants also argue that "[ n ]othing in Harris could lead one skilled in the art to recognize that FcRn-mediated transcytosis could be useful to transport nanoparticles including therapeutic, diagnostic or prognostic agents across the endothelial cell layer." Id. at 51-52. This argument is not persuasive because, for the reasons discussed previously, we conclude that Blumberg, Presta, Maruyama, and Farokhzad would have made obvious polymeric nanoparticles with multiple FcRn binding partners having at least 80% homology to SEQ ID NO: 1 on their surfaces, as well as FcRn-mediated transcytosis of nanoparticles that include a therapeutic agent across an endothelial cell layer. Therefore, we do not find any deficiency in the teachings of Blumberg, Presta, Maruyama, and Farokhzad with respect to the argued claim limitations. 21 Appeal2017-001466 Application 12/515,465 With regard to claims 15, 20, 27, 32, 36, 38, 39, 75, 76, and 78, Appellants argue that "at least for the reasons described above with respect to claims 112 and claims 114, Harris does not make up for the deficiencies of Blumberg, Presta, Farokhzad, Maruyama and Cheng." Appeal Br. 52. This argument is unpersuasive for the reasons discussed above. We therefore affirm the rejection of claims 15, 20, 27, 32, 36, 38, 39, 75, 76, 78, 112, and 114 under 35 U.S.C. § 103(a) based on Blumberg, Presta, Maruyama, Farokhzad, and Harris. V The Examiner has rejected claims 1, 115, and 117 under 35 U.S.C. § 103(a) as obvious based on Blumberg, Presta, Maruyama, either Farokhzad or Cheng, Harris, and Ruoslahti. With respect to claim 1, Appellants argue that "Ruoslahti does not make up for the deficiencies of Blumberg, Presta, Farokhzad, Maruyama, Harris and Cheng." Appeal Br. 53. For the reasons discussed above, however, we conclude that the nanoparticles of claim 1 would have been obvious based on the disclosures of Blumberg, Presta, Maruyama, and Farokhzad. We therefore do not find any deficiency in their disclosures that requires remedy by Harris. With respect to claim 115, 14 the Examiner finds that a "peptide comprising the sequence of CREKA selectively homes to tumor vascular" 14 Claim 115 is directed to "[t]he nanoparticle of claim 1, further comprising a targeting moiety on surface of the nanoparticle, wherein the targeting moiety is a peptide comprising CREKA (SEQ ID N0.:7) amino acid 22 Appeal2017-001466 Application 12/515,465 and "can be linked to polymeric matrix," and that "the homing properties of the CREKA to the tumor site would reduce the side effect associated with systemic delivery." Ans. 14. The Examiner concludes that it would have been obvious "to add CREKA peptide to the nanooparticle' s [sic] surface in order to target tumor vascular." Id. We agree with, and adopt, the Examiner's fact-finding and conclusion. Appellants argue that "Ruoslahti states that the five amino acid sequence CREKA ... interacts with all forms of collagen" and therefore "Ruoslahti does not teach or suggest a ligand that specifically binds collagen in the extracellular matrix of the basal lamina, as claimed." Appeal Br. 54-- 55. This argument is not persuasive, because claim 115 requires only that the nanoparticles comprise a CREKA-containing peptide as a targeting moiety, and that the peptide "binds to collagen IV." Claim 115 does not require the targeting moiety to bind "specifically" to collagen IV or exclude binding to other types of collagens. We therefore agree with the Examiner that the nanoparticles defined by claim 115 would have been obvious based on Blumberg, Presta, Maruyama, Farokhzad, Harris, and Ruoslahti. Claims 11 7 was not argued separately and therefore falls with claim 115. 37 C.F.R. § 4I.37(c)(l)(iv). sequence which binds to collagen IV and components thereof present in the extracellular matrix of the basal lamina." 23 Appeal2017-001466 Application 12/515,465 SUMMARY We reverse the rejections under 35 U.S.C. § 112, first paragraph, for lack of enablement and lack of adequate written description. We affirm all of the rejections under 35 U.S.C. § 103(a). 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 24 Copy with citationCopy as parenthetical citation