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 without traverse of Group I (indicated in Remarks as claims 1, 2, and 15) and the species of : (A) the configuration of (f) of instant claim 2; and (B) the ABP of (c) of instant claim 15 and Claim 1, Item (a): SEQ ID NO:109653; Claim 1, Item (b): SEQ ID NO:109688; Claim 1, Item (c): SEQ ID NO:109723; and Claim 1, Item (d): SEQ ID NO:109758 in the reply filed on 4 August 2025 is acknowledged. Applicant has indicated claims 1, 2, 15, 331, 334, 337, 340, 343 and 346 read upon the elected species.
Claims 325-330, 332-333, 335-336, 338-339, 341-342, 344-345, 347-348 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.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, 2, 15, 331, 334, 337, 340, 343 and 346 are examined upon their merits.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. (See “https…” on pgs. 70, 78, 96, 114, 123, 164, 198, 218, 223-225, 232-233, and 236.) 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.
Improper Markush Rejection
Claims 1, 2, and 15 are rejected on the basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984).
MPEP 2117(II) states: A Markush claim may be rejected under judicially approved "improper Markush grouping" principles when the claim contains an improper grouping of alternatively useable members. A Markush claim contains an "improper Markush grouping" if either: (1) the members of the Markush group do not share a "single structural similarity" or (2) the members do not share a common use. Supplementary Guidelines at 7166 (citing In re Harnisch, 631 F.2d 716, 721-22, 206 USPQ 300, 305 (CCPA 1980)). It further states, “a Markush grouping is ordinarily proper if all the members of the group belong to a recognized class”. The phrase “recognized class of chemical compounds” means that there is an expectation from the knowledge in the art that members of the class will behave in the same way in the context of the claimed invention, i.e. each member could be substituted one for the other, with the expectation that the same intended result would be achieved. The sequences listed in claims 1, 2, and 15 are not a single recognized class because there is no evidence of knowledge in the art that the alternatives could be substituted for one another.
Additionally, MPEP 2117(II)(B) states: “Where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as explained in subsection II.A, above, the members of the Markush grouping may still be considered to be proper where the alternatives share a substantial structural feature that is essential to a common use. The phrase “significant structural element is shared by all of the alternatives” refers to cases where the compounds share a common chemical structure which occupies a large portion of their structures, or in case the compounds have in common only a small portion of their structures, the commonly shared structure constitutes a structurally distinctive portion in view of existing prior art, and the common structure is essential to the common property or activity. In the instant case, for example, the alternatives (I) through (IV) within Claim 1 share no common structure as is evident by the following elected claimed sequences:
For part (I) SEQ ID NO: 109653 CARGNPWELRLDYW
For part (II) SEQ ID NO: 109688 CQQYYSYPFTF
For part (III) SEQ ID NO: 109723
QVQLVQSGAEVKKPGASVKVSCKASGYTFTNYYMHWVRQAPGQGLEWMGMINPSGGGTSYAQKFQGRVTMTRDTSTSTVYMELSSLRSEDTAVYYCARGNPWELRLDYWGQGTLVTVSS
For part (IV) SEQ ID NO: 109758
DIQMTQSPSSLSASVGDRVTITCQASQDISNYLNWYQQKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQYYSYPFTFGPGTKVDIK
The Markush groupings of Claims 1, 2, and 15 are improper because the alternatives defined by the Markush groupings do not share a single structural similarity OR a common use that flows from significant structural similarity. This is further evidenced by the fact that the alternatives of (I) through (IV) constitute different antibody fragments CDR-H3, CDR-L3, VH and VL, respectively.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity.
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, 2, 15, 331, 334, 337, 340, 343 and 346 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.
Claim 1 recites an (scFv)2 Fab diabody (where the two scFVs are identical) or tribody (where the two scFVs bind the same antigen but are derived from different antibodies), yet the claim sets forth “a CDR-H3” which is singular, “a CDR-L3” which is singular, “a VH sequence” also singular or “a VL sequence” singular (Claim 1, parts (I) through (IV), respectively). This recitation renders unclear the scope of the multispecific ABP because, as depicted in Figure B below, even a diabody, in which the scFVs are the identical (see Figure B below only VL3 = VL2 and VH3 = VH2), has more than a singular VH, more than a singular VL, and all of these features are required and should not be recited in the alternative. Therefore, the claim renders the scope of the invention indefinite. This affects the scope of all depending claims (claims 2, 15, 331, 334, 337, 340, 343 and 346).
Claim 2 is further indefinite when read in light of the specification and claim 1. As stated above, claim 1 sets forth a singular CDR-H3, a singular CDR-L3, a singular VH sequence or a singular VL sequence. The elected configuration of claim 2 (part f), however, states: “wherein the VL domain of the first scFv interacts with the VH domain of the second scFv and wherein the VH domain of the first scFv interacts with the VL domain of the second scFv”. It is unclear how an ABP with, “a VH sequence” which is singular or “a VL sequence” which is singular can now have two VH and VL domains. This claim fails to further limit the scope of the parent claim, but is more broad than the parent claim.
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(adapted from Mertens, N. (2011) Tribodies: Fab–scFv Fusion Proteins as a Platform to Create Multifunctional Pharmaceuticals. In: Kontermann, R. (eds) Bispecific Antibodies. Springer, Berlin, Heidelberg)
Similarly, Claim 15 recites “the VH domain” of the first scFv may contain an amino acid substitution; “the VH domain of the second scFv” may contain an amino acid substitution; or, both may contain substitutions; and the same for VL domains. Again, the parent claim, Claim 1 recites a singular VH sequence or a singular VL sequence. Thus, it is unclear how a molecule originally claimed as having one VH or VL recited in the alternative, can now have more than one of each. This claim is more broad than the parent claim.
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, 2, 15, 331, 334, 337, 340, 343 and 346 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The specification fails to disclose how to make a multispecific antigen-binding protein (ABP) comprising a first scFv and a second scFv that each specifically bind NTDNNLAVY (SEQ ID NO: 109455), a Fab that specifically binds an additional a second target antigen that is distinct from the first target antigen, and an Fc domain.
Regarding the epitope of NTDNNLAVY (SEQ ID NO: 109455), the specification teaches: [001058] “literature review was carried out for peptides” and [001059] “One notable example from Table C was KKLC1 HLA-A*01:01_ NTDNNLAVY (SEQ ID NO: 109455). Kita-kyushu lung cancer antigen-1 (KK-LC-1; CT83) is a cancer testis antigen (CTA) that has been shown to be widely expressed in many different cancer types. It was originally discovered based on a cloned CTL to KK-LC-1 peptide 76-84 — RQKRILVNL (SEQ ID NO: 110149) (Fukuyama et al., 2006). More recently Stevanovic et al., 2017 revealed another peptide from KK-LC-1 recognized by a CTL in a patient with cervical cancer, the predicted peptide KK-LC-1 52-60 NTDNNLAVY (SEQ ID NO: 109455). The corresponding TCR for this CTL is now listed on the NIH website https://www.ott.nih.gov/technology/e-153- 2016/ and the peptide is listed in WO 2017/089756 A1, herein incorporated by reference, in its entirety, for all purposes. [001060] This example highlights the expected value of predicted HLA-PEPTIDE targets in Table A: Although no information on which CTA HLA-PEPTIDE targets were previously known was incorporated in the prediction, the analysis yielded many targets that were described in the literature, indicating that many of the novel targets can likewise be validated experimentally and ultimately serve as targets for one or more ABPs”.
There appears to be no actual reduction to practice of any ABP comprising two scFVs that each bind the NTDNNLAVY (SEQ ID NO: 109455) epitope, in conjunction with a Fab and Fc region.
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 require a genus of ISV-based drugs and corresponding variants that are essentially identical to the ISV-based drugs, yet the inventors have disclosed the amino acid sequences of only two ISV-based drugs and two associated variants.
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; and given the unpredictability within the art with respect to creating antibodies. A person having ordinary skill in the art would have to perform further experimentation in order to make the scFVs and Fab encompassed by the scope of the claims. Given the nature of the invention, a skilled artisan would have to make multiple variants of ABP, with and without amino acid substitutions (see claim 15), in order to validate their function each binding “to an HLA-PEPTIDE target comprising an HLA-restricted peptide complexed with an HLA Class I molecule, and wherein the HLA-restricted peptide is located in the peptide binding groove of an a1/a2 heterodimer portion of the HLA Class I molecule, the HLA Class I molecule is HLA subtype A*01:01 and the HLA-restricted peptide comprises the sequence NTDNNLAVY (SEQ ID NO: 109455)” with a reasonable expectation of success. The amount of experimentation required to make the ABP of the claims and demonstrate functional binding, goes beyond what is considered “a reasonable degree of experimentation” and constitutes undue further experimentation in order to enable the invention as claimed.
For all of these reasons, the specification does not enable the claims, and Claims 1, 2, 15, 331, 334, 337, 340, 343 and 346 are rejected under 35 U.S.C. 112(a).
Conclusion
No claim is allowed.
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
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