DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amended claims filed May 28, 2026 with the Response to the non-final Office Action are acknowledged. Claim 19 has been canceled. Claims 13, 16-17, 21, and 26-27 are amended. Claims 29-30 are newly added.
Claims 13, 16-17, 21-27, and 29-30 are pending and under examination herein.
WITHDRAWN OBJECTIONS AND REJECTIONS
The objection to the specification is withdrawn in view of Applicant's amendment to page 18 as filed May 28, 2026.
All prior rejections of claim 19 are rendered moot by the cancelation of the claim.
The rejection of claims 21 and 27 under 35 U.S.C. § 112(d) is withdrawn in view of Applicant's amendments to the claims.
MAINTAINED REJECTIONS AND NEW REJECTIONS NECESSITATED BY AMENDMENT
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 23 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention. This is a new rejection necessitated by claim amendment.
Claim 23 depends from the method of claim 19, which is canceled as of May 28, 2026. Accordingly, the intended claim scope cannot be determined and the claim is indefinite.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 13, 16-17, 21-22, 24-27, and 29-30 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a maintained rejection that has been updated based on Applicant's amendments to the claims.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[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, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification.
The claimed invention. The nature and scope of the claimed invention at issue in part is a method for inhibiting a biological activity of a B cell activating factor (BAFF) polypeptide in a subject (as recited in claims 13 and 16). The method comprises contacting the BAFF polypeptide in the subject with an effective amount of a monoclonal anti-BAFF antibody, wherein the monoclonal anti-BAFF antibody binds to an epitope having the amino acid sequence of SEQ ID NO: 2 (and comprising the amino acid sequence of SEQ ID NO: 1) present within the BAFF polypeptide to inhibit BAFF multimerization substantially without depletion of mature B cells in the subject. The anti-BAFF antibody recited in the claimed method is described in terms of its functions of binding to the BAFF epitope corresponding to the amino acid sequence of SEQ ID NO: 2 and inhibiting BAFF multimerization substantially without depletion of mature B cells, without reciting a corresponding structure that would be expected to perform the claimed function.
Similarly at issue are the claimed methods for inhibiting growth of abdominal aortic aneurysm (AAA) (as recited in claim 17 and its dependent claims) and for treating a B cell-related condition (as recited in claim 26 and its dependent claims). Both methods comprise the step of administering to a subject in need thereof an effective amount of a composition comprising a monoclonal anti-BAFF antibody, wherein the anti-BAFF antibody inhibits multimerization of the BAFF polypeptide substantially without depletion of mature B cells in a subject and binds to an epitope having amino acid sequence KVHVFGDELSLVT (SEQ ID NO: 2). The anti-BAFF antibody recited in the instantly claimed methods is defined only by its functional activity without describing a corresponding structure that would be expected to correlate with said functions.
State of the prior art. Schroeder and Cavacini (Journal of Allergy and Clinical Immunology (2010) 125(2, Suppl.2): S41-S52; cited in PTO-892 mailed October 1, 2024) teach that conventional immunoglobulins (antibodies) known in the art are composed of two heavy and two light chains. These chains can be separated functionally into variable domains, which are responsible for antigen binding, and constant domains, which specify effector functions (Abstract). Each variable domain (heavy and light) can be split into three regions of sequence variability (i.e., CDRs). The six heavy and light chain CDRs are paired to form the antigen-binding site as classically defined (Abstract). It is understood in the art that, for a conventional antibody or immunoglobulin, the structural element that correlates with its function is these six CDRs. As discussed by Sela-Culang et al. (Frontiers in Immunology (2013) 4: 302; cited in PTO-892 mailed October 1, 2024), “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3, left column, “CDRs Identification”).
Gershoni et al. (Biodrugs (2007) 21(3): 145-156; cited in PTO-892 mailed October 1, 2024) teach that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence. Further, the state of the art recognizes that it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes that are dictated by the unique interaction between an antibody and its cognate epitope (Blythe et al., Protein Science (2005) 14:246-248 at page 246; cited in PTO-892 mailed October 1, 2024).
Several inhibitory anti-BAFF antibodies are known in the art, including belimumab, tabalumab, and others (e.g., as disclosed in Navarra et al. (2011) The Lancet 377(9767): 721-731; Isenberg et al. (2016) Annals of the Rheumatic Diseases 75(2): 323-331; Baker et al. (2003) Arthritis & Rheumatology 48(11): 3253-3265; US 2015/0218267 A1; US 6,869,605 B2; all of which are cited in PTO-892 mailed October 1, 2024). Shin et al. (Nature Communications (2018) 9:1200; cited in IDS) teach that belimumab binds an epitope within the DE loop of BAFF (also known as the “flap” region), which is partially hidden within the structure of the BAFF 60-mer, and disrupts the formation of BAFF 60-mer to favor the induction of the less active BAFF trimer form (Abstract; Figure 2; page 3). Whereas belimumab does not potently bind the 60-mer form, tabalumab binds both the 60-mer and trimer forms without disrupting the oligomeric states of BAFF, implying that its epitope would be completely exposed on the surface of the 60-mer (Abstract, Nicoletti et al. The Journal of Pharmacology and Experimental Therapeutics (2016) 359: 37-44, cited in IDS; Shin et al., page 3). Despite these differences, belimumab and tabalumab both deplete mature B cells in humans (Applicant’s disclosure, page 80, lines 1-3). Lymphostat-B, a fully human monoclonal antibody against BAFF (also called B lymphocyte stimulator, BLyS), also depletes B cells in cynomolgus monkeys (Baker et al., 2003).
Scope of species disclosed in original specification. The specification describes a polyclonal “anti-DE3 Ab” from which monoclonal anti-DE antibodies were generated (Examples 1 and 9). The anti-DE3 antibody was raised against a peptide comprising SEQ ID NO: 2 (Example 9). Example 10 recites that “by way of example,” polyclonal and monoclonal anti-BAFF antibodies were generated against multiple lengths comprising the BAFF DE loop (KVHVFGDELS, SEQ ID NO: 1) and neighboring amino acids (SEQ ID NO: 3-11).
According to the disclosure, the polyclonal anti-DE3 antibody specifically binds the DE loop of BAFF, does not affect the population of mature B cells, and suppresses expression of B cell activation markers (Examples 5 and 9; Figures 9-10). It is unclear from the disclosure how many monoclonal anti-DE antibodies were generated. Further, the corresponding structures (e.g., amino acid sequences of the antigen-binding domains) for the disclosed anti-DE antibodies are not disclosed.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. As recited above, the specification describes an anti-DE3 polyclonal antibody raised against the BAFF epitope comprising the amino acid sequence of SEQ ID NO: 2. It is unclear from the disclosure how many monoclonal antibodies were generated from the polyclonal antibody population. The state of the art recognizes that hundreds of antibodies against a single antigen can be created. Accordingly, the disclosure of a single species cannot be said to be representative of the broad genus of anti-BAFF antibodies that bind specifically to the BAFF epitope comprising the amino acid sequence of SEQ ID NO: 2.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As illustrated by the state of the art, corresponding CDR structures in the heavy chain variable region (VH) and light chain variable region (VL) are critical for conferring the functional antigen binding properties of the antibody. However, the instant specification is silent with respect to the structure of the disclosed anti-DE antibody or antibodies that would be expected to correlate with the function of binding to the BAFF polypeptide at the epitope comprising SEQ ID NO: 2. Furthermore, the state of the art recognizes that one cannot predict the structure of an antibody knowing only the epitope to which it binds. Thus, one of ordinary skill in the art would be unable to visualize or recognize the members of the genus for an antibody that “binds to an epitope having amino acid sequence KVHVFGDELSLVT (SEQ ID NO: 2) present within the BAFF polypeptide” as instantly claimed.
Furthermore, at least one other inhibitory anti-BAFF antibody, belimumab, is known in the art that, like the instantly claimed antibody, binds an epitope in the DE loop of BAFF, but unlike the instantly claimed antibody, purportedly depletes B cells. This discrepancy between the state of the art and the antibody recited in the present disclosure further speaks to the necessity of disclosing relevant identifying structural characteristics that would allow the skilled artisan to understand why one anti-BAFF antibody that binds the DE loop of the BAFF polypeptide depletes B cells while the other does not.
Conclusion. For all of the reasons presented above, one of skill in the art would not know which of the countless other antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of antibodies as broadly claimed at the time the application was filed.
Response to Arguments
Applicant's arguments filed May 28, 2026 have been fully considered but they are not persuasive.
Applicant submits that “the Office Action improperly elevates one particular category of structural information, namely CDR sequence information, into a de facto written description requirement, contrary to controlling precedent and the guidance set forth in MPEP §2163”. Applicant states that “M.P.E.P. §2163 recognizes that written description may be demonstrated through various forms of identifying characteristics, including structural features, physical properties, functional characteristics coupled with a known or disclosed correlation, and combinations of identifying characteristics”, and that it is not a “legal requirement that CDR sequence information must be disclosed in every monoclonal antibody written-description analysis.” Remarks at pages 8-9.
Applicant argues that the application discloses “multiple experimentally identified and characterized embodiments that define monoclonal antibodies being use [sic] to indirectly target a specific population of B cells, that being undifferentiated, non-matured B cells, through binding of the soluble, extracellular protein BAFF”, including defining the epitope sequence corresponding to SEQ ID NO: 1 and peptide variants containing flanking residues thereof. Remarks at page 9. Applicant further submits that a PHOSITA “would be able to ascertain the details through which a monoclonal antibody is produced using hybridoma technology” based on the specification and publicly available information from the Antibody Engineering and Technology Core at University of Virginia, thereby demonstrating “actual possession and reduction to practice”. Remarks at page 9. Applicant submits that they have disclosed “experimentally characterized properties associated with the claimed monoclonal antibodies”, e.g., flow cytometry data presented in Figure 9, which serve to distinguish the instantly claimed invention. Remarks at page 10.
In response, it is maintained that the state of the prior art makes clear that one cannot readily predict or visualize which members of the genus of monoclonal anti-BAFF antibodies that bind to an epitope of BAFF comprising the amino acid sequence of SEQ ID NO: 2 that also possess the functional activity of inhibiting BAFF multimerization substantially without depletion of mature B cells, as required in the claim, to be able to carry out the claimed methods. As demonstrated by the example of belimumab, the art recognizes that there are anti-BAFF antibodies which bind to the same epitope as that instantly claimed but do deplete mature B cells. It is the physical structures of each antibody, at minimum that of the antigen-binding domains, which confer these functional differences between the two anti-BAFF antibodies. Applicant's assertion about the lack of an established “legal requirement that CDR sequence information must be disclosed in every monoclonal antibody written-description analysis” does not take into consideration that the facts of each case, across diverse art areas, requires an independent analysis. The minimum structure required to satisfy the written description requirement will differ among different art areas. With respect to the biological art relevant to the instantly claimed invention, it is understood that binding of an antibody to a distinct antigen – and especially to a particular epitope of said antigen – is unpredictable, but the minimum structure required to achieve this function is well understood. Furthermore, it is understood that just because an antibody binds to a particular epitope does not mean it inherently possesses other functional qualities, as demonstrated by the comparison of belimumab and the instantly claimed antibody. Ultimately, the “experimentally characterized properties” described by Applicant in the disclosure are all functional properties that do not by their nature demonstrate “structural features, physical properties, functional characteristics coupled with a known or disclosed correlation, and combinations of identifying characteristics” as set forth in MPEP § 2163 that are sufficient to establish that Applicant possessed a representative genus of the monoclonal anti-BAFF antibodies recited in the presently claimed methods. Neither the epitope bound by an antibody, nor its ability to inhibit BAFF multimerization substantially without depleting mature B cells, nor the fact that the antibody is monoclonal, provides implicit information about its accompanying structure. Applicant's disclosure does not remedy this deficiency.
Furthermore, even if one of ordinary skill in the art recognized at the time of filing of the instantly claimed invention that monoclonal anti-BAFF antibodies having the instantly claimed functional properties could be generated using hybridoma technology, following the example of the disclosure and/or publicly available information from the Antibody Engineering and Technology Core at University of Virginia, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad, 94 USPQ2d at 1167; Centocor at 1876 ("The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody"). Applicant's arguments appear to assume that by following art-recognized methods for generating monoclonal antibodies, one would consistently generate identical replicates of those antibodies obtained by the Applicant possessing the same functional attributes. However, absent information about the structure of the antibodies generated by the Applicant, how would one of ordinary skill in the art recognize that these exact same antibodies have in fact been generated?
It is maintained that for the rejected claims to satisfy the written description requirement, the claims must further recite the basic structural features of said antibodies that are responsible for conferring these functional attributes (such as, the heavy chain and light chain CDRs or a biological deposit of the disclosed antibody). The disclosure does not specifically enumerate such a structure or biological deposit for any specific embodiment of the invention.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
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