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 .
Election/Restrictions
Applicant's election with traverse of Group I and the species of CTLA4 and ADCC in the reply filed on 9 January 2026 is acknowledged. The traversal is on the ground(s) that claims 11 and 12 should be rejoined. This is not found persuasive because product and process inventions are different categories of invention. However, since Applicant has elected the product for initial prosecution, if an allowable product is identified the method claims comprising said allowable product will be rejoined and examined according to Rejoinder Practice.
The requirement is still deemed proper and is therefore made FINAL.
Claims 11-14 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
Claims 1-9 and 16 are examined upon their merits.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is the national stage entry of PCT/EP2021/083595 filed on 30 November 2021, and claiming the benefit of European Patent application Nos. EP21166846.2, filed 2 April 2021 and EP20211335.3 filed 2 December 2020.
Claims 1-9 and 16 have an effective US filing date of 2 December 2020.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 1 June 2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01. Specifically, executable code appears on pages 2 and 3 of the specification wherein it cites https://doi.org/10.1007/s00262-020-02583-y and (Sainson et al. 2019, https://doi.org/10.1101/771493).
Claim Rejections - 35 USC § 112
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.
Claims 1-9 and 16 are 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.
Claims 2-7, 9 and 16 are indefinite because they recite a product and process in the same claim. MPEP 2173.05(p)(II) states: “A single claim which claims both an apparatus and the method steps of using the apparatus is indefinite under 35 U.S.C. 112, second paragraph.” See In re Katz Interactive Call Processing Patent Litigation, 639 F.3d 1303 (Fed. Cir. 2011). In Katz, a claim directed to “A system with an interface means for providing automated voice messages…to certain of said individual callers, wherein said certain of said individual callers digitally enter data” was determined to be indefinite because the italicized claim limitation is not directed to the system, but rather to actions of the individual callers, which creates confusion as to when direct infringement occurs. In re Katz, 639 F.3d at 1318 (citing IPXL Holdings v. Amazon.com, Inc., 430 F.2d 1377, 1384, 77 USPQ2d 1140, 1145 (Fed. Cir. 2005), in which a system claim that recited “an input means” and required a user to use the input means was found to be indefinite because it was unclear “whether infringement … occurs when one creates a system that allows the user [to use the input means], or whether infringement occurs when the user actually uses the input means.”); < Ex parteLyell, 17 USPQ2d 1548 (Bd. Pat. App. & Inter. 1990) (claim directed to an automatic transmission workstand and the method of using it held ambiguous and properly rejected under 35 U.S.C. 112, second paragraph). The case law applies to the instant claim(s) which are directed to a combination product that “has cytotoxic activity” (claims 2 and 9); induces antibody-depending cellular cytotoxicity (claim 5); and, ADCC activity (claims 6-7 and 16). It is unclear if infringement of the product requires assessing the claimed activity or functionality of the product. This affects the scope of all claims that depend from claim 2.
The terms “increase” or ”increasing” in claims 6 and 16 are relative terms which render the claims indefinite. The terms are not defined by the claim itself (such as increase relative to a control), nor does the specification provide a standard for ascertaining the requisite degree of increase/increasing. Therefore, one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
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 1-9 and 16 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.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Claim 1 recites “a lymphotoxin beta receptor agonist” and “a regulatory T cell depletor”. Claims 2-9 and 16 are dependent from Claim 1, do not further limit the agonist or depletor in terms of material/structure, and are therefore included in the rejection. The claims do not require that the “agonist” and “depletor” possess any particular structure or other distinguishing feature. Additionally, claim 16 recites an ADCC increasing mutation that also has no structure or distinguishing feature. The claims are drawn to genera of agonists and depletors molecules in combination, and a genus of mutations.
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 (see MPEP 2163(II)(3)(a)( i)(A), reduction to drawings MPEP 2163(II)(3)(a) (i)(B), or 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 MPEP 2163(II)(3)(a) (i)(C). See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406.
In the instant case, the only factor present in the claim is a recitation of requisite activities (agonist activity, depletor activity, binding to a cell surface marker, having cytotoxic activity, and antibody-dependent cellular cytotoxicity activity). There is not even identification of any particular portion of a structure that must be conserved for any activity. Regarding the combination agonist/depletor of the claims, the specification discloses “P002MP07G04” a mouse LTBR-Fc monovalent and “VHH-16” which is a tetravalent VHH combining three P002MP07G04 and one anti-serum albumin building block separated by a 20GS flexible linker (pg. 54). The specification teaches only one bispecific combination that fulfills the functional requirements of the instant claims: a Treg depleting anti-CTLA4 in combination with an the LTBR agonist of VHH-16 (pg. 56, Example 7).
The Federal Circuit (Federal Circuit) decided in Amgen v. Sanofi, 872 F.3d 1367 (Fed. Cir. 2017), that disclosure of an antigen characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional. See Amgen Inc. v. Sanofi, 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017)("knowledge of the chemical structure of an antigen [does not give] the required kind of structure-identifying information about the corresponding antibodies"); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1351-52, 97 USPQ2d 1870, 1877 (Fed. Cir. 2011)(patent disclosed the antigen the claimed antibody was supposed to bind, but did not disclose any antibodies with the specific claimed properties). See MPEP 2163.II.A.3(a). The Amgen case law is applicable to the instant claims which are drawn to a bispecific antibody that is claimed solely by the antigens to which it binds.
In view of the Amgen decision, the instant claims fail to meet the requirements for disclosure because the antibody is described solely by the antigen to which it binds – LTBR and the instantly-elected CTLA4. Thus, the specification fails to provide adequate written description for the genera of bispecific antibodies encompassed by the instant claims, and fails to prove a representative number of species within the claimed genera.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites.
Therefore, in view of the Amgen case law, Claims 1-9 and 16 are rejected since they fail to provide all 6 CDR structures.
Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claims 1-9 and 16 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the Treg depleting anti-CTLA4 in combination with an the LTBR agonist of VHH-16 (pg. 56, Example 7), does not reasonably provide enablement for any other combination comprising a Lymphotoxin Beta Receptor (LTBR) agonist; and a regulatory T cell (Treg) depletor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
In AMGEN INC. ET AL. v. SANOFI ET AL. (No. 21-757, decided May 18, 2023), the Supreme Court held that Amgen was not enabled for “the entire genus” of antibodies that (1) “bind to specific amino acid residues on PCSK9,” and (2) “block PCSK9 from binding to [LDL receptors]” (872 F. 3d 1367, 1372) even though Amgen identified the amino acid sequences of 26 antibodies that perform these two functions.
The case law applies to the instant claims which encompass a genus of Lymphotoxin Beta Receptor (LTBR) agonists and a genus of regulatory T cell (Treg) depletors, yet the inventors have disclosed only one species within this genus a Treg depleting anti-CTLA4 antibody in combination with an the LTBR agonist antibody of VHH-16 (pg. 56, Example 7).
In Amgen, the Supreme Court has stated:
“An antibody’s structure does much to dictate its function—its ability to bind to an antigen and, in some instances, to block other molecules in the body from doing the same. ‘For an antibody to bind to an antigen, the two surfaces have to fit together and contact each other at multiple points.’ Id., at 11. But just because an antibody can bind to an antigen does not mean that it can also block. To bind and block, the antibody must establish a sufficiently broad, strong, and stable bond to the antigen. See ibid. Different antibodies have different binding and blocking capacities based on the amino acids that compose them and their three-dimensional shapes. See id., at 11–12.
Despite recent advances, aspects of antibody science remain unpredictable. For example, scientists understand that changing even one amino acid in the sequence can alter an antibody’s structure and function. See id., at 14. But scientists cannot always accurately predict exactly how trading one amino acid for another will affect an antibody’s structure and function. Ibid.”
Given that structure is essential to function, given that no structure is provided by the specification, and given the unpredictability within the art with respect to creating antibodies; person having ordinary skill in the art would have to perform further experimentation in order to make the genus of combinations encompassed by the claims and screen them to ensure that they fulfill the functional language recited by the instant claims (i.e. agonist activity, depletor activity, binding to a cell surface marker, having cytotoxic activity, and antibody-dependent cellular cytotoxicity activity).
The nature of the preferred embodiment of the invention is a bispecific antibody. A skilled artisan would have to make multiple combinations of a Lymphotoxin Beta Receptor (LTBR) agonist antibody; and a regulatory T cell (Treg) depletory antibody, and test them each for functionality in order to make and use the invention commensurate in scope with the breadth of the claims. This amount of experimentation goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the method for the breadth of what is claimed.
For all of these reasons, the specification does not enable the claims, and Claims 1-9 and 16 are rejected under 35 U.S.C. 112(a).
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 1-9 and 16 are rejected under 35 U.S.C. 103 as being unpatentable over US PGPub 2006/0104971 A1 published 18 May 2006 (hereafter Garber et al.) in view of Selby et al. 2013, NPL citation No. 3 on the IDS filed 1 June 2023.
The Garber et al. prior art reference discloses Multivalent Lymphotoxin Beta Receptor Agonist antibodies (see Figure 8) that inhibit the proliferation of human colon adenocarcinoma tumor cells (Figure 9).
The Garber et al. reference is silent with respect to an anti-CTLA4 antibody Treg depletor, but the Selby et al. reference remedies this deficiency. Selby et al. disclose antitumor anti-CTLA4 antibodies and Selby and colleagues state CTLA-4 loss or inhibition on regulatory T cells (Treg) results in reduced Treg function and contributes to antitumor responses by anti-CTLA4 antibody treatment (Abstract).
Section 2144.06 of the MPEP provides guidance as to obviousness of art recognized equivalents for the same purpose. The court has held that it is obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose. No specific teaching or suggestion is needed for combination – the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose. See In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
The Kerkhoven case law applied to the invention of the instant claims because the separate references disclose Lymphotoxin Beta Receptor Agonist antibodies as cytotoxic to cancer cells, and anti-CTLA4 antibodies as having antitumor activity as well. It would have been obvious to a person having ordinary skill in the art, before the effective filing date of the application, to combine these two antitumor compositions into one composition. No specific teaching or suggestion is needed for said combination because the idea of combining them flows logically from their having been individually taught in the prior art as useful for the same purpose – namely, antitumor.
Therefore, the combination invention of the claims is obvious in view of the obviousness of combining art recognized equivalents that are useful for the same purpose, Claims 1-9 and 16 are rejected.
Conclusion
No claim is allowed.
Correspondence
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STACEY NEE MACFARLANE whose telephone number is (571)270-3057. The examiner can normally be reached M-F 7:30-5 (EST) & Sat. A.M..
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/STACEY N MACFARLANE/Examiner, Art Unit 1675