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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on November 3, 2025 has been entered.
Application Status
The amended claims filed November 3, 2025 are acknowledged. Claims 13, 17, and 26 are amended. Claim 28 is canceled. Claims 13, 16-17, 19, and 21-27 are pending and under examination herein.
It is noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate about substantive issues with an authorized representative for the Applicant during the prosecution of the case.
Objections to the Claims Withdrawn
All prior objections to claim 28 are rendered moot by the cancelation of the claim.
The objection to claims 13 and 16 is withdrawn in view of Applicant's amendment of claim 13.
Claim Rejections Withdrawn
All prior rejections to claim 28 are rendered moot by the cancelation of the claim.
The rejection of claim 17 under 35 U.S.C. § 112(b) on the basis that it contains an improper Markush Group is withdrawn in view of Applicant's amendments to remove the recitation of “and/or a BAFF DE loop mimetic peptide”.
The rejection of claims 26-27 under 35 U.S.C. 102 as being anticipated by Brodeur (US 2015/0218267 A1) is withdrawn in view of Applicant's amendments to claim 26.
The rejection of claims 17, 21-23, and 25 under 35 U.S.C. § 103 as being unpatentable over Navarra (The Lancet (2011) 377(9767): P721-731) in view of Shin (Nature Communications (2018) 9:1200; cited in IDS) and Schaheen (Arteriosclerosis, Thrombosis, and Vascular Biology (2016) 36(11): 2191-2202; cited in IDS) is withdrawn in view of Applicant's amendments to claim 17.
OBJECTIONS AND REJECTIONS BASED ON RECONSIDERATION OF THE CLAIMS
Specification (New)
The disclosure is objected to because the amino acid sequence corresponding to SEQ ID NO: 2 as recited on page 88, line 13, appears to contain an extra C-terminal “C” residue. The sequence should instead recite “KVHVFGDELSLVT” based on the Sequence Listing of record.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 19, 21, and 27 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. This is a new rejection necessitated by claim amendment.
Claim 19 recites the method of claim 17, wherein “the composition inhibits BAFF multimerization substantially without depletion of mature B cells.” However, claim 17 as presently amended already recites that the composition comprising an anti-BAFF antibody inhibits BAFF multimerization substantially without depletion of mature B cells (lines 4-8). Thus, claim 19 does not further limit the subject matter of the claim upon which it depends.
Claim 21 recites the method of claim 17, wherein the anti-BAFF antibody (comprised in the composition administered in the method) “binds to an epitope present within a DE loop of a BAFF polypeptide and/or comprising a subsequence thereof.” This limitation does not include all of the limitations of the claim from which it depends. The method of amended claim 17 earlier recites that the anti-BAFF antibody “binds to an epitope having amino acid sequence KVHVFGDELSLVT (SEQ ID NO: 2) present within the BAFF polypeptide”, which comprises the DE loop (‘KVHVFGDELS’ or SEQ ID NO: 1) and additional C-terminal residues “LVT” that are part of the surrounding BAFF polypeptide structure based on Applicant's disclosure (page 91, lines 20-22). Therefore, Claim 21 recites that the antibody binds different epitope(s) such that the antibody does not include the epitope-related limitations of claim 17, so claim 21 does not include all of the limitations of the previous claim.
Claim 27 recites the method of claim 26, wherein “the B cell-related condition comprises a condition selected from the group consisting of an abdominal aortic aneurysm (AAA), a cardiovascular disease, lupus, type 1 diabetes, type 2 diabetes, and a B-cell related cancer” (a closed grouping). However, the previous claim sets forth that the “B cell-related condition is selected from the group consisting of a cardiovascular disease, type 1 diabetes, type 2 diabetes, and a B-cell related cancer” (also a closed grouping, but with fewer members). Claim 27 fails to include all of the limitations of the previous claim and fails to narrow the scope of the previous claim because the dependent claim sets forth that the B cell-related condition is selected from a larger grouping of possible conditions that includes lupus and AAA, which were not set forth in the previous claim.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
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, 19, and 21-27 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 an anti-BAFF antibody, wherein the anti-BAFF antibody binds to an epitope having the amino acid sequence of SEQ ID NO: 2 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 claim). Both methods comprise the step of administering to a subject in need thereof an effective amount of a composition comprising an 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”, or a subsequence thereof, 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 November 3, 2025 have been fully considered but they are not persuasive.
Applicant argues that the instant claims do not specifically recite that the anti-BAFF antibodies are monoclonal antibodies. Applicant submits that the application as filed discloses, in some embodiments, a polyclonal antisera, and that monoclonal antibodies were not specifically generated. Applicant further argues that those of ordinary skill in the art recognize that polyclonal antisera include many antibodies that typically bind to different epitopes within a given antigen, and that “the Office’s assertions with respect to the unpredictability of the specificities of individual monoclonal antibodies appears to be irrelevant with respect to the instantly claimed subject matter”. Remarks at page 6.
In response, it is held that the instant claims are drawn to a broad genus of anti-BAFF antibodies, including both monoclonal and polyclonal antibodies. These antibodies are specifically defined by their functional attributes, i.e., binding to a BAFF polypeptide epitope “having amino acid sequence … SEQ ID NO: 2” and inhibiting BAFF multimerization substantially without depletion of mature B cells. The state of the prior art makes clear that one cannot predict or visualize all of the members of such a genus of anti-BAFF antibodies that possess these functional attributes knowing only that the antibody is specific for BAFF. MPEP § 2163 (II)(A)(3)(a)(ii) states in relevant part: “("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). "A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed." This lack of unpredictability is underscored by the comparison of Applicant's disclosed anti-DE3 antibody(-ies) to belimumab, which binds to the same epitope as the antibody recited in the instantly claimed method but depletes B cells.
In order for the rejected claims to satisfy the written description requirement, the claims would need to 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). However, the disclosure does not specifically enumerate such a structure or biological deposit for any specific embodiment of the invention.
For these reasons, the rejection is maintained.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Elizabeth A Shupe whose telephone number is (703)756-1420. The examiner can normally be reached Monday to Friday, 9:00am - 5:30pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Julie Wu can be reached at (571) 272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643