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 .
Applicant’s amendment, filed on 12/15/2023, is acknowledged.
Claims 1, 3, 9, 18-20, 24, 25, and 27 are cancelled.
Claims 2, 4-8, 10-17, 21-23, and 26 are currently pending.
Claim 2 is an independent claim.
Election/Restrictions
Applicant’s election of Group I, claims 2, 4-8, 10-17, and 26, drawn to a molecule comprising a polypeptide chain; and the Species of: i) the polypeptide chain of claim 2(b); ii) IgG1; and linkers of the same length in the reply filed on 6/16/2026 is acknowledged. Because applicant did not distinctly and specifically point out the supposed errors in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Claim 13 reads on an unelected species of linker length (i.e., linkers of different lengths).
Claims 13 and 21-23 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
Claims 2, 4-8, 10-12, 14-17, and 26 are under examination as being drawn to a molecule comprising a polypeptide chain with the arrangement recited in claim 2(b).
Priority
Applicant’s claim for the benefit of a prior-filed U.S. Provisional Application No. 63/121,166, filed December 3, 2020, is acknowledged.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 10/17/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner in its entirety.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter "Legal Framework") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation-by-reference of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the specification are not identified by sequence identifiers in accordance with 37 CFR 1.821(d).
Specifically, amino acid sequences are disclosed in the specification in ¶[0042], [0054]-[0056], [0058], [00119], [00200]
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required sequence identifiers, consisting of:
A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
A copy of the amended specification without markings (clean version); and
A statement that the substitute specification contains no new matter.
Specification
The disclosure is objected to because the specification discloses an error message in ¶[00204] that should most likely be deleted. Appropriate correction is required.
The use of the terms:
SelectSure™ (¶[00204]);
Gibco™ (¶[00210]); and
Graphpad Prism™ (¶[00218]);
which are trade names or marks used in commerce, has been noted in this application. The term should be accompanied by the generic terminology; furthermore the term should be capitalized wherever it appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Claim Objections
Claim 5 is objected to because the claim recites “…alterations that extends half life” and should most likely recite “…alterations that extend serum half-life.” to correct minor typographical errors.
Claim Rejections - 35 USC § 112
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 2, 4-8, 10-12, 14-17, and 26 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 claims contain 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 inventors, at the time the application was filed, had possession of the claimed invention.
Claims 2, 4-8, 10-12, 14-17, and 26 encompass a broad genus of single chain immunoglobulin Fc (scFc) regions with no recited structure and the recited function of “half-life extension moiety”.
Claims 14 and 15 additionally encompass a broad genus of polypeptides with a partial structure at best and the recited functions of “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 14) or “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 15).
However, the specification fails to provide adequate written description support for a genus of scFc molecules with a partial structure at best to practice the claimed function of “half-life extension moiety” (claims2, 4-8, 10-12, 14-17, and 26); or polypeptides with a partial structure at best and the functions of “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 14) or “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 15).
The claims are not supported by a description that satisfies 35 U.S.C. § 112(a) or 35 U.S.C. § 112, first paragraph. "[T]he test for sufficiency [of the written description] is whether the disclosure of the application relied upon reasonably conveys to those skilled in the art that the inventor had possession of the claimed subject matter as of the filing date." Ariad Phanns., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en bane).
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." Id. at 1350. "[A]n adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials." Id.
"[F]unctional claim language can meet the written description requirement when the art has established a correlation between structure and function." Id. "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 that one has invented a genus and not just a species." Id.
"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" (AbbVie, 759 F.3d at 1297, reiterating Eli Lilly, 119 F.3d at 1568-69) (emphasis added).
The specification discloses generation and expression of trispecific tetravalent binding polypeptides comprising four scFv molecules with an single-chain Fc region in two different formats, (HHLL)2 and (HLHL)2, referring to the arrangement of the scFv VH and VL regions (Example 1, Fig. 1, and ¶[00199] and [00200]):
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The specification discloses that these polypeptides comprise one VH/VL sequence pair from a scFv that targets cadherin-3, one VH/VL sequence pair from a scFv sequence that targets mesothelin, and two copies of a VH/VL sequence pair from a scFv that targets CD3 (¶[0199]-[0200], Tables 3 and 4). The VH and VL sequences of the anti-MSLN 15-B12 scFv clone are SEQ ID NO: 39 and 40, respectively, the VH and VL sequences of the anti-CDH3 15-E11 scFv clone are SEQ ID NO: 43 and 44, respectively, and the VH and VL sequences of the anti-CD3 6H10-09 scFv clone are SEQ ID NO: 41 and 42, respectively.
The specification discloses one example of a single-chain Fc region to increase serum half-life (¶[00244], SEQ ID NO: 54).
The instant specification discloses that the (HHLL)2 and (HLHL)2 formats of these binding polypeptides have similar expression levels (Tables 3 and 4), with the (HHLL)2 format yielding slightly lower concentrations than the (HLHL)2 antibody format (¶[00201]): “…production runs for both T6M and G7Q are provided in Tables 3 and 4, respectively, and demonstrate comparable protein yields for both molecules”. The protein stability of these constructs were not tested.
With respect to representative number of species, see AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014). Also, see MPEP 2163 Il(A)(3)(a))(ii):
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. 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. See Abb Vie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus.").
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are "representative of the full variety or scope of the genus," or by the establishment of "a reasonable structure-function correlation." Such correlations may be established "by the inventor as described in the specification," or they may be "known in the art at the time of the filing date." See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014) (Holding that claims to all human antibodies that bind IL-12 with a particular binding affinity rate constant (i.e., koff) were not adequately supported by a specification describing only a single type of human antibody having the claimed features because the disclosed antibody was not representative of other types of antibodies in the claimed genus, as demonstrated by the fact that other disclosed antibodies had different types of heavy and light chains, and shared only a 50% sequence similarity in their variable regions with the disclosed antibodies.).
In the instant case, regarding the broadly claimed genus of scFc constructs with a partial structure at best and the recited function of “half-life extension moiety” (claims 2, 4-8, 10-12, 14-17, and 26), the instant specification only discloses one version of a functional single-chain Fc region, while the instant claims encompass a much broader genus of scFc polypeptides comprising widely varying polypeptide sequences with this function in which this one example does not sufficiently represent. For example, the instant claims encompass single-chain Fc regions with any length and type of linker that would give rise to properly folded scFc regions with the function of “half-life extension moiety”
Additionally, regarding the broadly claimed genera of polypeptides with a partial structure at best and the functions of “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 14) or “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 15), the instant specification does not disclose any example of a polypeptide with these functions. The instant specification only discloses one example of a polypeptide that has comparable expression levels to other formats (Tables 2 and 3, SEQ ID NO: 37).
Moreover, there is insufficient written description of the required kind of structure-identifying information about the corresponding makeup of the claimed antigen binding constructs to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). The Court reiterated that adequate written description must “contain enough information about the actual makeup of the claimed products . . . .” The Court simultaneously suggested that the “newly characterized antigen” test “flouts” section 112 because it “allows patentees to claim antibodies by describing something that is not the invention, i.e., the antigen.” The Court concluded that for written description of an antibody to be adequate when presented with “functional” terminology, there must be an established correlation in the art between structure and function.
Given the broadly claimed classes of half-life extension moieties and polypeptides with the recited stability/expression functions, and in the absence of sufficient disclosure of relevant identifying characteristics for the broadly claimed classes of scFcs/polypeptides, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc. (Fed. Cir. 2014), MPEP 2163.
Regarding the broadly claimed genus of scFc constructs with a partial structure at best and the recited function of “half-life extension moiety” (claims 2, 4-8, 10-12, 14-17, and 26), the instant specification does not disclose any structure-function relationship between an scFc’s structure, defined by its polypeptide sequence, and the function of “half-life extension moiety”. Additionally, the prior art teaches that there is unpredictability in generating functional scFc constructs. For example, Zhou et al. (Biomaterials. 2017 Feb;117:24-31. doi: 10.1016/j.biomaterials.2016.11.051) teaches that the linker between different scFc domains plays an important role in proper expression and assembly of an scFc, as rigid linkers would not allow for proper Fc assembly (Introduction): “[a] flexible, rather than a rigid, linker was used in this study to allow the two Fc domains to interact properly with eachother.” Additionally, Zhou et al. teaches that smaller linkers lead to improper Fc assembly and monomer formation instead of a functional scFc (Fig. 2 and Section 3.1).
Other than disclosing specific polypeptide sequences that form functional scFc structures with the function “half-life extension moiety”, neither the instant specification nor the prior art provides sufficient structure-function relationship between a does not provide any structure-function relationship between a single-chain Fc region’s amino acid sequence and the function of “half-life extension moiety”.
Regarding the broadly claimed genera of polypeptides with a partial structure at best and the functions of “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 14) or “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” (claim 15), neither the instant specification nor the prior art discloses or teaches sufficient structure-function relationship between a polypeptide’s structure, defined by its amino acid sequence, and the functions recited in claims 14 and 15. The instant specification does not disclose any way to distinguish between polypeptide structures with these functions from ones without. The instant specification does not list any examples of polypeptides with these functions as well.
Possession is not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. Sufficient description to show possession of such a genus may be achieved by means of a recitation of a representative number of scFc regions with the function of “half-life extension moiety” and polypeptides with the stability/expression functions recited in the claims falling within the scope of the genus or of a recitation of structural features common to members of the genus, which features constitute a substantial portion of the genus. See Eli Lilly, 119F.3d at 1568, 43 USPQ2d at 1406.
Claims 2, 4-8, 10-12, 14-17, and 26 do not meet the requirements of 35 U.S.C. 112(a) for written description.
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.). Consequently, Applicant was not in possession of the instant claimed invention. See University of California v. Eli Lilly and Co. 43 USPQ2d 1398.
Applicant is invited to point to clear support or specific examples of the claimed invention in the specification as-filed.
To overcome this rejection, it is recommended to amend claim 2 to recite specific disclosed scFc structures with the function of “half-life extension moiety”, and specific polypeptide structures (if any) with the recited functions of “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4” and/or “enhanced stability as compared to a molecule having a structure of VH1-Linker-VL1-Linker-VH2-Linker-VL2-Linker-Half-Life Extending Moiety-VH3-Linker-VL3-Linker-VH4-Linker-VL4”.
Claims 2, 4-8, 10-12, 14-17, and 26 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 polypeptides comprising the VH and VL sequences of the anti-MSLN scFv clone 15-B12 with the function of “anti-mesothelin”, the VH and VL sequences of the anti-CDH3 scFv clone 15-E11 with the function of “anti-mesothelin”, and the paired VH and VL sequences of any of the anti-CD3 scFv clones 6H10.09, I2C, I2C_44/100cc, I2E, I2L, and/or I2M2 with the function of “anti-CD3”, does not reasonably provide enablement for a broadly claimed genus of polypeptides with a partial structure at best with the functions of “bind to an immune effector cell” and “bind to a target cell”. 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 use the invention commensurate in scope with these claims.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
Breadth of claims and nature of invention:
Claims 2, 4-8, 10-12, 14-17, and 26 encompass a broad genus of agents with no recited structure (claims 2, 4-6, 8, 10-12, 14-17, and 26) or a partial structure at best (claim 7) with both of the functions of “bind to an immune effector cell” and “bind to a target cell”.
The instant specification discloses trispecific T-cell engagers comprising a single polypeptide comprising the VH/VL sequences from the anti-mesothelin scFv clone 15B12, the VH/VL sequences from the anti-CDH3 scFv clone 15-E11, and two copies of the VH/VL sequences from the anti-CD3 scFv clone 6H10.09, as well as a single chain Fc domain (Example 1).
Amount of direction and existence of working examples:
The format was either in an (HHLL)2 or (HLHL)2 arrangement (Fig. 1B and 1A, respectively, see supra). Both constructs were found to bind to mesothelin/CDH3 dual positive tumor cells and recruit CD3+ T-cells to engage the T-cells to target the tumor cells in vitro, however the (HHLL)2 version had had greater activity towards cells that express one of the two antigens (Fig. 5 and 6, Fig. 5 below):
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Two examples of different scFv structures that bind to a target cell are disclosed by the instant specification, which are the anti-MSLN scFv clone 15 B12 (VH and VL of SEQ ID NO: 39 and 40, respectively), and the anti-cadherin-3 scFv clone 15-E11 (VH and VL of SEQ ID NO: 43 and 44, respectively).
Multiple examples of different scFv structure that bind to an immune effector cell are all different clones of anti-CD3 scFvs, which are 6H10.09 (VH and VL of SEQ ID NO: 41 and 42, respectively), I2C (VH and VL of SEQ ID NO: 64 and 65, respectively), I2C_44/100cc (VH and VL of SEQ ID NO: 72 and 73, respectively), I2E (VH and VL of SEQ ID NO: 80 and 81, respectively), I2L (VH and VL of SEQ ID NO: 88 and 89, respectively), and I2M2 (VH and VL of SEQ ID NO: 96 and 97, respectively).
Level of predictability, state of prior art, and quantity of experimentation needed:
The claims are directed to polypeptides comprising VH and VL regions with a partial structure at best with the functions of “bind to an immune effector cell” and “bind to a target cell”, which includes a broad genus of millions to billions of VH/VL pairs with little to no recited structure, all with the recited functions. The specific VH/VL pairs, and their antigen targets, are not defined.
However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of millions of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses one example of a VH/VL pair with the function of “anti-MSLN” (the scFv clone 15 B12), and one VH/VL pair with the function of “anti-CDH3” (the scFv clone 15-E11), and 6 different VH/VL pairs with the function of “anti-CD3” (the scFv clones 6H10.09, I2C, I2C_44/100cc, I2E, I2L, and I2M2). No scFv clones that had the broad function of “binds to an immune effector cell” or “binds to a target cell” were disclosed.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
In the instant case, the claims are directed to polypeptides comprising broad classes of VH/VL pairs with a partial structure at best and the functions of “bind to an immune effector cell” and “bind to a target cell”.
The instant claims are directed to classes of polypeptides that include “a ‘vast’ number” of additional structures (i.e., amino acid sequences of all of the CDR regions or the VH/VL regions that are necessary for antigen binding in the case of antibodies) in which the instant specification fails to describe. It would be necessary to first generate and then screen each candidate polypeptide to determine whether or not it met the function limitations of “bind to an immune effector cell” and “bind to a target cell”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which other polypeptide structures would have the functions of “bind to an immune effector cell” and “bind to a target cell”. The only structure-function relationship guidance the specification provides is to disclose individual examples of scFv structures that bind to different epitopes found to target cells, such as MSLN and CHD3; and examples of scFv structures that bind to CD3 found on T-cells.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antibody structures they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
Applicant is relying upon certain biological activities such as scFv structures that bind to specific epitopes found on target cells and specific epitopes found on an immune effector cell (i.e., T-cell) and a limited number of species with defined structures (e.g. amino acid sequences) to support an entire genus of diverse and structurally unrelated inhibitory polypeptide structures. Yet the instant specification does not provide sufficient guidance and directions as to the structural features of the polypeptide structures and the correlation between the structure and the desired antigen binding and inhibitory function.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to make and use the invention of instant claims 2, 4-8, 10-12, 14-17, and 26. The specification does enable one with ordinary skill to make the antibody clone discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
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 7 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.
Claim 7 currently recites: “…wherein the VH2 and VH4 sequence comprise SEQ ID NO: 41 and the VL2 and VH4 sequence comprise SEQ ID NO: 42.”. However, the instant specification discloses that SEQ ID NO: 42 is a VL sequence (¶[0232]). It is currently unclear how a VH domain can comprise a VL sequence. For the purposes of examination, the claim is interpreted to have VL2 and VL4 sequences comprising instant SEQ ID NO: 42.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 2, 4, 6, 8, 10-12, 16, 17, and 26 are rejected under 35 U.S.C. 103 as being unpatentable over Ellwanger et al. (WO2017064221) in view of Zhou et al (Biomaterials. 2017 Feb;117:24-31. doi: 10.1016/j.biomaterials.2016.11.051), as evidenced by Couzi et al. (Blood. 2012 Feb 9;119(6):1418-27. doi: 10.1182/blood-2011-06-363655) and Morath et al. (J Leukoc Biol. 2020 Jun;107(6):1045-1055. doi: 10.1002/JLB.2MR1219-233R).
Claim 2 recites molecules comprising a polypeptide chain having the structure of the elected species recited in claim 2b), wherein the linkers are at least 10 amino acids in length, and wherein the molecules binds to an immune effector cell and a target cell, and wherein the half-life extending moiety is an scFc.
Ellwanger et al. teaches multispecific polypeptides comprising different pairs of VH and VL regions (Abstract), including the following format (Fig. 4):
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Ellwanger et al. teaches that the polypeptide has linkers between each of the VH/VL domains (pg. 23, lines 13-18). Ellwanger et al. teaches lengths of linkers can range, for example, between 5 and 50 amino acids in length (pg. 9, lines 2-6): “…peptide linkers are used…(G3S)x peptide linkers are used, wherein, for example, x = 1-15 or (G4S)x peptide linkers are used, wherein, for example, x = 1-10, preferably 1-6. The amino acid sequence of the linker can be optimized, for example, by phage-display methods to improve the antigen binding and production yield of the polypeptide.” Ellwanger et al. teaches embodiments of linkers that are 12 residues in length (Claim 5).
Ellwanger et al. teaches the multispecific polypeptides can act as immune cell engagers that target CD16, CD30, and EGFRvIII (pg. 29, lines 5-9). Ellwanger et al. teaches that CD30 and EGFRvIII are tumor cell (i.e., “target cell”) markers (pg. 19, lines 11-14): “[e]xamples of specificieties for tumor cells include…CD30…EGFRvIII…” Ellwanger et al. additionally teaches that CD16 is found on immune cells such as NK cells (i.e., “immune effector cell”; pg. 18, line 23): “…CD16A (FcγRIIIA) antigen is a receptor expressed on the surface of NK cells…”.
Ellwanger et al. teaches single polypeptide chains comprising four VH and 4 VL regions connected by linkers (Figure 4), which are in the following order: VL1-L-VH1-L-VL2-L-VH2-L-VL3-L-VL4-L-VH3-L-VH4. However, Ellwanger et al. teaches in Figure 4 that the VH/VL pairings can have alternative arrangements where the first 2 VH/VL pairs have the order of H-H-L-L and the second two VH/VL pairs have the order of H-H-L-L, leading to the order recited in instant claim 2(a).
Ellwanger et al. does not teach the polypeptide chains additionally comprising an scFc half-life extension moiety (i.e., the limitations of the elected species of claim 2(b)).
Zhou et al., in the same field of endeavor, teaches development of a single-chain Fc region (Introduction): “…we have designed and evaluated a novel type of Fc fusion protein by using a long, flexible glycine-serine (GS) linker to link two Fc chains, with the hinge sequence removed, to create a single chain Fc-dimer, sc(Fc)2…” Zhou et al. additionally teaches that polypeptide fusions with this scFc region have increased half-life than fusions proteins comprising a WT Fc dimer (Discussion): “…the half-life of hGH-sc(Fc)2 was about 2-times longer than hGH-Fc following intravenous injection in CF1 mice (Fig. 7B). The shorter half-life of hGH-sc(Fc)2 compared to sc(Fc)2 could be a result of its lower binding to FcRn observed by SPR…”
Zhou et al. teaches (Conclusion): “…novel carrier protein showed significant improvements in half-life and bioactivity of the protein drug cargo compared with traditional Fc-based drug carrier. sc(Fc)2 technology has the potential to greatly improve and expand the use of Fc-technology for improving the pharmacokinetics of protein drugs.”
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the invention of Ellwanger et al. in view of Zhou et al. to generate a multivalent scFv binding polypeptide with an scFc half-life extension domain with a reasonable expectation of success, as Zhou et al. teaches scFc protein fusion that one with ordinary skill would be able to apply to the polypeptides taught by Ellwanger et al. One would have been motivated to make this change for the purposes of extending the serum half-life of the multispecific targeting polypeptides taught by Ellwanger et al.
Regarding the arrangement of the VH, VL, and scFc regions, one with ordinary skill in the art would try multiple different positions to integrate/rearrange the scFc, including the N and C termini, or in between paired VH/VL groups, such as position 4 in Fig. 4. Also see MPEP 2144.04(VI)(C). The arrangement with the scFc in between VH/VL groups, with the VH VH VL VL arrangement taught by Ellwanger et al. discussed supra would lead to a polypeptide comprising VH1-L-VH2-L-VL1-L-VL2-L-scFc-L-VH3-L-VH4-L-VL3-L-VL4, wherein the linkers are 12 amino acid residues in length. Ellwanger et al. additionally teaches the polypeptide can target CD30, EGFRvIII, and CD16, meeting the limitations of instant claim 2.
Regarding instant claim 4, Zhou et al. further teaches that the scFc2 from human IgG1 (Section 2.2.1): “…pFUSE-hIgG1-Fc2 contains the DNA sequence of CH2 and CH3 domains of wild-type hIgG1…”, meeting the claim limitations.
Regarding instant claim 6, Ellwanger et al. teaches that the polypeptide can be tetraspecific (pg. 35, line 35 to pg. 36, line 2). For example, the polypeptide of SEQ ID NO: 14 and 15 comprise VH and VL regions from 4 different scFv structures that bind to CD30, CD16, CD19, and EGFRvIII, each of which have different VH/VL sequences which could be rearranged into the format taught by Ellwanger in Fig. 4. This would lead to VH1, VH2, VH3, VH4, VL1, VL2, VL3, and VL4 regions that all have different sequences, meeting the claim limitations.
Regarding instant claim 8 and 10-12, Ellwanger et al. teaches that the linkers can all be 12 amino acids in length (i.e., all the same length), meeting the claim limitations.
Regarding instant claim 16, Couzi et al. is provided as an evidentiary reference to demonstrate that CD16 is expressed on γδ T-cells (Abstract): “[t]he observation that CD16 (FcγRIIIA) was specifically expressed by the majority of HCMV-induced γδ T cells…”, and the γδ TCR is part of the TCR-CD3 complex, meeting the claim limitations.
Regarding instant claim 17, Morath et al. is provided as an evidentiary reference to demonstrate that γδ T-cells expressing the γδTCR-CD3 complex, which includes the CD3ε chain (Fig. 1), meeting the claim limitations.
Regarding instant claim 26, Ellwanger et al. teaches pharmaceutical compositions comprising the polypeptide (pg. 21, lines 13-15), meeting the claim limitations.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Claim 5 is rejected under 35 U.S.C. 103 as being unpatentable over Ellwanger et al. (supra) in view of Zhou et al (supra), as evidenced by Couzi et al. (supra) and Morath et al. (supra), as applied to claims 2, 4, 6, 8, 10-12, 16, 17, and 26 above, and further in view of Lo et al. (J Biol Chem. 2017 Mar 3;292(9):3900-3908. doi: 10.1074/jbc.M116.767749).
The teachings of Ellwanger et al. in view of Zhou et al., as evidenced by Couzi et al. and Morath et al. have been discussed supra. The combined references do not teach the scFc region having alterations that inhibit FcγR binding (i.e., the limitations of instant claim 5).
Lo et al., in the same field of endeavor, teaches the L234A, L235A, and P329G Fc mutations to eliminate antibody Fc region binding to FcγR (Abstract): “…we found an L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-γ-dependent, antibody-dependent, cell-mediated cytotoxicity in both murine IgG2a and human IgG1…” Lo et al. teaches a method of making such mutant Fc regions (“Experimental Procedures”), and the mutations lead to reduced toxicity in vivo (Fig. 4-6).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the combined references of Ellwanger et al. in view of Zhou et al., as evidenced by Couzi et al. and Morath et al. further in view of Lo et al. to introduce the L234A, L235A, and P329G Fc into the scFc of the multispecific polypeptide construct taught by the combined references with a reasonable expectation of success, as Lo et al. teaches human IgG1 Fc mutations that could be easily be applied to the IgG1 scFc of Zhou et al. One would have been motivated to make this change to reduce the in vivo toxicity of the polypeptide construct taught by Ellwanger et al. in view of Zhou et al., as evidenced by Couzi et al. and Morath et al.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2, 7, 8, 10-12, 16, 17, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 11, 13-22, 26, 27, 29, 30, 32-51, 55, 58, and 60 of copending Application No. 18/251,196 (App ‘196) in view of Ellwanger et al. (WO2017064221, supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘196 claims antigen binding molecules comprising one polypeptide chain comprising a first, second, third, and fourth binding domains, wherein there is a scFc in between the second and third binding domains (claim 1). App ‘196 claims the first and third binding domains bind to a target cell surface antigen (i.e., “target cell”), and the second and fourth binding domains bind to CD3ε (i.e., “immune effector cell”; App ‘196 claim 1). App ‘196 claims that the binding domains all comprise antibody variable domains (claim 16).
App ‘196 does not claim specific polypeptide domain VH/VL arrangements with linkers.
Ellwanger et al., in the same field of endeavor, teaches multispecific polypeptides comprising different pairs of VH and VL regions (Abstract), including the following format (Fig. 4):
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Ellwanger et al. teaches that the polypeptide has linkers between each of the VH/VL domains (pg. 23, lines 13-18). Ellwanger et al. teaches lengths of linkers can range, for example, between 5 and 50 amino acids in length (pg. 9, lines 2-6): “…peptide linkers are used…(G3S)x peptide linkers are used, wherein, for example, x = 1-15 or (G4S)x peptide linkers are used, wherein, for example, x = 1-10, preferably 1-6. The amino acid sequence of the linker can be optimized, for example, by phage-display methods to improve the antigen binding and production yield of the polypeptide.” Ellwanger et al. teaches embodiments of linkers that are 12 residues in length (Claim 5).
Ellwanger et al. teaches single polypeptide chains comprising four VH and 4 VL regions connected by linkers (Figure 4), which are in the following order: VL1-L-VH1-L-VL2-L-VH2-L-VL3-L-VL4-L-VH3-L-VH4. However, Ellwanger et al. teaches in Figure 4 that the VH/VL pairings can have alternative arrangements where the first 2 VH/VL pairs have the order of H-H-L-L and the second two VH/VL pairs have the order of H-H-L-L, leading to the order recited in instant claim 2(a).
It would have been obvious to one with ordinary skill in the art to have modified App ‘196 in view of Ellwanger et al. to arrange the VH/VL domains of the four binding domains (with 12aa linkers in between) in the HHLL with a reasonable expectation of success, as Ellwanger et al. teaches multispecific binding polypeptides with such arrangements. One would have been motivated to do so to rearrange the known parts of the binding peptide claimed by App ‘196 to optimize the binding and/or therapeutic properties of the polypeptide claimed by App ‘196.
The resulting arrangement from this would be VH1-L-VH2-L-VL1-L-VL2-L-scFc-VH3-L-VH4-L-VL3-L-VL4-L, with linkers of 12 residues, which are the limitations of instant claim 2.
Regarding claim 7, App ‘196 claims the second and fourth VH comprise SEQ ID NO: 67, and the second and fourth VL comprise SEQ ID NO: 68. SEQ ID NO: 67 of App ‘196 is 100% identical to instant SEQ ID NO: 41:
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SEQ ID NO: 68 of App ‘196 is 100% identical to instant SEQ ID NO: 42 (i.e., the limitations of instant claim 7):
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Regarding claims 8 and 10-12, Ellwanger et al. teaches the linkers are all the same length of 12 residues, meeting the claim limitations.
Regarding claims 16 and 17, App ‘196 claims the second and fourth binding domains bind CD3ε, meeting the claim limitations.
Regarding instant claim 26, Ellwanger et al. teaches pharmaceutical compositions comprising the polypeptide (pg. 21, lines 13-15), meeting the claim limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘196 in view of Ellwanger et al., especially in absence of evidence to the contrary. This is a provisional double patenting rejection.
Claims 4 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 6, 11, 13-22, 26, 27, 29, 30, 32-51, 55, 58, and 60 of copending Application No. 18/251,196 (App ‘196) in view of Ellwanger et al. (supra), as applied to claims 2, 7, 8, 10-12, 16, 17, and 26 above, and further in view of Lo et al. (J Biol Chem. 2017 Mar 3;292(9):3900-3908. doi: 10.1074/jbc.M116.767749 supra).
The teachings of Ellwanger et al. in view of Zhou et al., as evidenced by Couzi et al. and Morath et al. have been discussed supra. The combined references do not teach the scFc region as an hIgG1 isotype having alterations that inhibit FcγR binding (i.e., the limitations of instant claims 4 and 5).
Lo et al., in the same field of endeavor, teaches the L234A, L235A, and P329G Fc mutations to eliminate antibody Fc region binding to FcγR (Abstract): “…we found an L234A, L235A, P329G (LALA-PG) variant that eliminates complement binding and fixation as well as Fc-γ-dependent, antibody-dependent, cell-mediated cytotoxicity in both murine IgG2a and human IgG1…” Lo et al. teaches a method of making such mutant Fc regions (“Experimental Procedures”), and the mutations lead to reduced toxicity in vivo (Fig. 4-6).
It would have been obvious to one with ordinary skill in the art, before the effective filing date of the instant application, to have modified the combined references of App ‘196 in view of Ellwanger et al. further in view of Lo et al. to introduce the L234A, L235A, and P329G human IgG1 Fc into the scFc of the multispecific polypeptide construct taught by the combined references with a reasonable expectation of success, as Lo et al. teaches human IgG1 Fc mutations that could be easily be applied to the IgG1 scFc of Zhou et al. One would have been motivated to make this change to reduce the in vivo toxicity of the polypeptide construct of App ‘196 in view of Ellwanger et al.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘196 in view of Ellwanger et al., and further in view of Lo et al., especially in absence of evidence to the contrary. This is a provisional double patenting rejection.
Claims 2, 4, 8, 10-12, 16, 17, and 26 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 18/251,133 (App ‘133) in view of Ellwanger et al. (supra) and Zhou et al (Biomaterials. 2017 Feb;117:24-31. doi: 10.1016/j.biomaterials.2016.11.051, supra). Although the claims at issue are not identical, they are not patentably distinct from each other.
App ‘133 claims antigen binding molecules comprising one polypeptide chain comprising a first, second, third, and fourth binding domains, wherein there is a half-life extension moiety in between the second and third binding domains (claim 17). App ‘133 claims the first and third binding domains bind to a target cell surface antigen (i.e., “target cell”), and the second and fourth binding domains bind to CD3ε (i.e., “immune effector cell”; App ‘133 claim 17). App ‘133 claims that the binding domains all comprise antibody variable domains (claim 17).
App ‘133 does not claim specific polypeptide domain VH/VL arrangements with linkers, or the half-life extension moiety comprising an scFc comprising human IgG1 (i.e., the limitations of instant claims 2 and 4)
Ellwanger et al., in the same field of endeavor, teaches multispecific polypeptides comprising different pairs of VH and VL regions (Abstract), including the following format (Fig. 4, see supra). Ellwanger et al. teaches that the polypeptide has linkers between each of the VH/VL domains (pg. 23, lines 13-18). Ellwanger et al. teaches lengths of linkers can range, for example, between 5 and 50 amino acids in length (pg. 9, lines 2-6): “…peptide linkers are used…(G3S)x peptide linkers are used, wherein, for example, x = 1-15 or (G4S)x peptide linkers are used, wherein, for example, x = 1-10, preferably 1-6. The amino acid sequence of the linker can be optimized, for example, by phage-display methods to improve the antigen binding and production yield of the polypeptide.” Ellwanger et al. teaches embodiments of linkers that are 12 residues in length (Claim 5).
Ellwanger et al. teaches single polypeptide chains comprising four VH and 4 VL regions connected by linkers (Figure 4), which are in the following order: VL1-L-VH1-L-VL2-L-VH2-L-VL3-L-VL4-L-VH3-L-VH4. However, Ellwanger et al. teaches in Figure 4 that the VH/VL pairings can have alternative arrangements where the first 2 VH/VL pairs have the order of H-H-L-L and the second two VH/VL pairs have the order of H-H-L-L, leading to the order recited in instant claim 2(a).
Zhou et al., in the same field of endeavor, teaches development of a single-chain Fc region (Introduction): “…we have designed and evaluated a novel type of Fc fusion protein by using a long, flexible glycine-serine (GS) linker to link two Fc chains, with the hinge sequence removed, to create a single chain Fc-dimer, sc(Fc)2…” Zhou et al. additionally teaches that polypeptide fusions with this scFc region have increased half-life than fusions proteins comprising a WT Fc dimer (Discussion): “…the half-life of hGH-sc(Fc)2 was about 2-times longer than hGH-Fc following intravenous injection in CF1 mice (Fig. 7B). The shorter half-life of hGH-sc(Fc)2 compared to sc(Fc)2 could be a result of its lower binding to FcRn observed by SPR…”
Zhou et al. teaches (Conclusion): “…novel carrier protein showed significant improvements in half-life and bioactivity of the protein drug cargo compared with traditional Fc-based drug carrier. sc(Fc)2 technology has the potential to greatly improve and expand the use of Fc-technology for improving the pharmacokinetics of protein drugs.”
It would have been obvious to one with ordinary skill in the art to have modified App ‘133 in view of Ellwanger et al. to arrange the VH/VL domains of the four binding domains (with 12aa linkers in between) in the HHLL with a reasonable expectation of success, as Ellwanger et al. teaches multispecific binding polypeptides with such arrangements. One would have been motivated to do so to rearrange the known parts of the binding peptide claimed by App ‘133 to optimize the binding and/or therapeutic properties of the polypeptide claimed by App ‘133. Additionally, it would have been obvious to use the scFc half-life extension moiety taught by Zhou et al. in the invention claimed by App ‘133, as Zhou et al. teaches a functional half-life extension moiety that can be used in the invention claimed by App ‘133.
The resulting arrangement from this would be VH1-L-VH2-L-VL1-L-VL2-L-scFc-VH3-L-VH4-L-VL3-L-VL4-L, with linkers of 12 residues, which are the limitations of instant claim 2.
Regarding instant claim 4, Zhou et al. further teaches that the scFc2 from human IgG1 (Section 2.2.1): “…pFUSE-hIgG1-Fc2 contains the DNA sequence of CH2 and CH3 domains of wild-type hIgG1…”, meeting the claim limitations.
Regarding claims 8 and 10-12, Ellwanger et al. teaches the linkers are all the same length of 12 residues, meeting the claim limitations.
Regarding claims 16 and 17, App ‘196 claims the second and fourth binding domains bind CD3ε, meeting the claim limitations.
Regarding instant claim 26, Ellwanger et al. teaches pharmaceutical compositions comprising the polypeptide (pg. 21, lines 13-15), meeting the claim limitations.
Therefore, the invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘133 in view of Ellwanger et al. and Zhou et al., especially in absence of evidence to the contrary. This is a provisional double patenting rejection.
Claim 5 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-29 of copending Application No. 18/251,133 (App ‘133) in view of Ellwanger et al. (supra) and Zhou et al (supra), as applied to claims 2, 4, 8, 10-12, 16, 17, and 26 above, and further in view of Lo et al. (supra).
The combined teachings of App ‘133 in view of Ellwanger et al. and Zhou et al., have been discussed supra. The combined references do not teach the scFc region as an hIgG1 isotype having alterations that inhibit FcγR binding (i.e., the limitations of instant claim 5).
The invention encompassed by the instant claims is a prima facie obvious variant of the invention claimed by App ‘133 in view of Ellwanger et al. and Zhou et al., and further in view of Lo et al. for the same reasons discussed for App ‘196 supra. This is a provisional double patenting rejection.
Conclusion
No claim is allowed.
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/ALEC JON PETERS/Examiner, Art Unit 1641
/MISOOK YU/Supervisory Patent Examiner, Art Unit 1641
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