DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Application Status
The amended claims filed April 14, 2023 are acknowledged. Claims 3-5, 7, 9, 12-13, 15-16, 19-20, and 22-23 are amended. No claims are canceled or newly added. Claims 1-23 are pending and under examination herein.
It is noted that a Power of Attorney is not on record for the instant application. The Applicant is encouraged to file a Power of Attorney in the event that the Examiner needs to communicate with an authorized representative for the Applicant during the prosecution of the case.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, 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 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 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 statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - The incorporation by reference paragraph required by 37 CFR 1.834(c)(1), 1.835(a)(2), or 1.835(b)(2) is missing, defective or incomplete. Specifically, the Incorporation by Reference Paragraph should list the file size in bytes, not kilobytes. See 1c above.
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 incorporation by reference paragraph, 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.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The disclosure is objected to because the specification appears to recite the incorrect IAPUC name for the compound corresponding to CAS No. 850664-21-0 (GSK269962A), e.g., the disclosure states that the compound comprises “[2-(morpholin-4-yl)ethoxy]” instead of “[2-(4-morpholinyl)ethoxy]”. See CAS data sheet in Office Action Appendix.
Appropriate correction is required.
Claim Objections
Claims 8, 14, and 21 are objected to for the following informalities:
Claim 8 is objected to because (1) “LByI35” should instead recite “LBY135” and (2) “WD-1” should instead recite “WD1”. See, e.g., Wang (Cellular & Molecular Immunology (2008) 5(1): 55-60) and Dubuisson (Antibodies (Basel) (2017) 6(4): 16).
Claims 14 and 21 are objected to because the claims should recite “a light chain variable region” in lines 2 and 3, respectively.
Appropriate correction is required.
Applicant is advised that should claims 10 and 12 be found allowable, claims 17 and 19 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
In the present case, the recitation of an intended use of the composition in the preamble, specifically “for use in treating a tumor and/or a cancer”, does not further limit the claim because the intended use does not result in a structural difference between the claimed compositions or between the claimed compositions and the prior art. See MPEP § 2111.02(II). Accordingly, there is no patentably distinct difference between the compositions recited in claims 10 and 12 and in claims 17 and 19.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-12, 14, and 17-23 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.
Regarding claim 1, the phrase “optionally” in line 5 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to “a checkpoint inhibitor” (genus) or more narrowly to the specific checkpoint inhibitors (species) set forth in lines 6-9.
Claims 2-9, which depend from claim 1, do not remedy this deficiency and are similarly rejected.
Further regarding claim 2, the phrase “optionally” in line 2 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to a solid tumor or more narrowly to the specific exemplary solid tumors recited in lines 2-4.
Further regarding claim 4, the IUPAC names corresponding to “GSK269” (GSK269962A) and “GSK429” (GSK429286A) appear to contain various typographical errors (e.g., “I” or “l”, i.e., uppercase India or lowercase Lima, in place of “1”, i.e., Arabic numeral one) and incorrect chemical moieties. For comparison, see CAS SciFinder data sheets in Office Action Appendix. For example, the claim recites a “trifhioromethyl” moiety in GSK429, which could be a typo for “trithiomethyl” or “trifluoromethyl”, each of which are chemically distinct.
Further regarding claim 4, the claim recites that the inhibitor of ROCK 1 activity is “selected from the group comprising … (GSK269) and … (GSK429)”, appearing to set forth an improperly formatted Markush grouping of alternatives. The claim scope is indefinite because it is unclear which other alternatives are intended to be encompassed by the claim. See MPEP § 2175.05(h)(I), which sets forth that a Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members.
Further regarding claim 5, the phrase “optionally” in line 2 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to any checkpoint inhibitor antibody or more narrowly to an antibody binding the specific immune checkpoint proteins as recited in lines 2-3.
Further regarding claim 8, the claim recites that the DR5 targeting antibody is “selected from the group comprising” a listing of alternative antibodies, appearing to set forth an improperly formatted Markush grouping of alternatives. The claim scope is indefinite because it is unclear which other alternatives are intended to be encompassed by the claim. See MPEP § 2175.05(h)(I), which sets forth that a Markush grouping is a closed group of alternatives, i.e., the selection is made from a group "consisting of" (rather than "comprising" or "including") the alternative members.
Further regarding claim 9, the phrase “optionally” in line 3 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to any checkpoint inhibitor or more narrowly to an immune checkpoint inhibitor that specifically targets an antigen recited in lines 4-6.
Regarding claim 10, the phrase “optionally” in line 4 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to any checkpoint inhibitor (genus) or more narrowly to the specific checkpoint inhibitors (species) set forth in lines 4-8.
Claims 11-12, which depend from claim 10, do not remedy this deficiency and are similarly rejected.
Claim 14 recites the limitation that the bispecific antibody of claim 13 comprises a heavy chain variable region (VH) and/or a light chain variable [sic] “as set forth in any of SEQ ID NOs: 1-12”. The bispecific antibody of claim 13 has a first antigen-binding site specific for death receptor 5 (DR5) and a second antigen-binding site specific for one of ROCK1, CTLA-4, PD-1, or PD-L1. As set forth in the instant disclosure, the antibody corresponding to farletuzumab, which comprises a VH having the amino acid sequence of SEQ ID NO: 12 and a VL having the amino acid sequence of SEQ ID NO: 11, specifically binds to FOLR1 (also called folate receptor 1, folate receptor alpha, FRα). See, e.g., page 13, lines 19-21; page 16, lines 22-23; page 67, lines 13-15; pages 94-97 and Table 7. The claim scope is indefinite because it’s unclear how an antigen-binding domain from a bispecific antibody comprising the VL comprising the amino acid sequence of SEQ ID NO: 11 and/or the VH comprising the amino acid sequence of SEQ ID NO: 12 can have specificity for any one of DR5, ROCK1, CTLA-4, PD-1, or PD-L1 when these sequences are drawn to antigen-binding domains having specificity for FOLR1.
Regarding claim 17, the phrase “optionally” in line 5 renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). The description of examples or preferences is properly set forth in the specification rather than the claims. Examples and preferences in a claim may lead to confusion over the intended scope of the claim. In the present instance, it is unclear whether the metes and bounds of the claim are limited more broadly to any checkpoint inhibitor (genus) or more narrowly to the specific checkpoint inhibitors (species) set forth in lines 5-9.
Claims 18-19, which depend from claim 17, do not remedy this deficiency and are similarly rejected.
Further regarding claim 18, the claim recites a composition comprising a bispecific antibody, wherein the first antigen-binding site is specific for the DR5 polypeptide and the second antigen-binding site is “specific for a ROCK1 polypeptide, a CTLA4 polypeptide, a PD-1 polypeptide, and/or a PD-L1 polypeptide”. Based on the “and/or” language, the claim is drawn to a second antigen-binding site that binds to more than one of the recited antigens. This limitation regarding the second antigen-binding site renders the claim scope indefinite because, as understood by those in the art, the antigen-binding domain of an antibody (e.g., a VH and VL in a conventional monoclonal antibody) together have specificity for a specific linear or conformational epitope on a single antigen, not multiple antigens. Thus, such an antigen-binding site would not be expected to bind to more than one of ROCK1, PD-1, PD-L1, or CTLA-4. Furthermore, if the antibody is “bispecific” (i.e., recognizes two antigens) as claimed, and one of the binding domains is required to be specific for DR5, then the other antigen-binding domain can only be specific for one additional antigen.
Regarding claim 20, the claim recites a bispecific antibody comprising a first “binding activity” that binds to a DR5 polypeptide and a second “binding activity” that binds to a ROCK1 polypeptide, a CTLA4 polypeptide, a PD-1 polypeptide, and/or a PD-L1 polypeptide”. Based on the “and/or” language, the claim is drawn to a second “binding activity” that binds to more than one of the recited antigens. This limitation regarding the second “binding activity” renders the claim scope indefinite because, as understood by those in the art, an antigen-binding domain of an antibody (e.g., a VH and VL in a conventional monoclonal antibody) together have specificity for a specific linear or conformational epitope on a single antigen, not multiple antigens. Thus, such an antigen-binding site would not be expected to bind to more than one of ROCK1, PD-1, PD-L1, or CTLA-4. Furthermore, if the antibody is “bispecific” (i.e., recognizes two antigens) as claimed, and one of the binding domains is required to be specific for DR5, then the other antigen-binding domain can only be specific for one additional antigen.
Claims 21-23, which depend from claim 20, do not remedy this deficiency and are similarly rejected.
Further regarding claim 21, the claim recites the bispecific antibody of claim 20, comprising a heavy chain variable region (VH) and/or a light chain variable [sic] “as set forth in any of SEQ ID NOs: 1-12”. The bispecific antibody of claim 20 has a first “binding activity” that binds to death receptor 5 (DR5) and a second “binding activity” that binds to a ROCK1 polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, and/or a PD-L1 polypeptide. As set forth in the instant disclosure, the antibody corresponding to farletuzumab, which comprises a VH having the amino acid sequence of SEQ ID NO: 12 and a VL having the amino acid sequence of SEQ ID NO: 11, specifically binds to FOLR1 (also called folate receptor 1, folate receptor alpha, FRα). See, e.g., page 13, lines 19-21; page 16, lines 22-23; page 67, lines 13-15; pages 94-97 and Table 7. The claim scope is indefinite because it’s unclear how a “binding activity” from a bispecific antibody comprising the VL comprising the amino acid sequence of SEQ ID NO: 11 and/or the VH comprising the amino acid sequence of SEQ ID NO: 12 can have specificity for any one of DR5, ROCK1, CTLA-4, PD-1, or PD-L1 when these sequences are drawn to antigen-binding domains having specificity for FOLR1.
It is noted for Applicant that “optional” limitations will not be considered required for the purpose of applying prior art under 35 U.S.C. § 102 and § 103.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 14 and 21 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
The teachings of claims 14 and 21 are summarized in the 35 U.S.C. § 112(b) rejections above. The claims fail to include the limitations of the claim from which they depend because a bispecific antibody comprising a heavy chain variable region (VH) that comprises an amino acid sequence of SEQ ID NO: 12 and/or a light chain variable region (VL) that comprises an amino acid sequence of SEQ ID NO: 11 would not be expected to specifically bind to any of DR5, ROCK1, PD-1, PD-L1, or CTLA-4, since these variable domains are derived from an antibody having specificity for FOLR1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 14 and 21 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.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
The claimed invention. The nature and scope of the claimed invention at issue in part is a bispecific antibody (as recited in claim 14) that binds to a DR5 polypeptide and to a second polypeptide selected from the group consisting of ROCK1, CTLA-4, PD-1, and PD-L1, wherein the bispecific antibody comprises “a heavy chain variable region and/or a light chain variable [region] as set forth in any of SEQ ID NOs: 1-12”. The specification (Table 7, pages 94-95) sets forth that:
SEQ ID NO: 1-2 correspond to the VL and VH of lexatumumab (anti-DR5 antibody),
SEQ ID NO: 3-4 correspond to the VL and VH of tigatuzumab (anti-DR5 antibody),
SEQ ID NO: 5-6 correspond to the VL and VH of AMG-655/conatumumab (anti-DR5 antibody),
SEQ ID NO: 7-8 correspond to the VL and VH of KMTR2 (anti-DR5 antibody),
SEQ ID NO: 9-10 correspond to the VL and VH of avelumab (anti-PD-L1 antibody), and
SEQ ID NO: 11-12 correspond to the VL and VH of farletuzumab (anti-FOLR1 antibody).
Further at issue is the bispecific antibody for use in treating a tumor and/or a cancer (as recited in claim 21), comprising a “first binding activity” that binds to a DR5 polypeptide and “a second binding activity” that binds to a ROCK1 polypeptide, a CTLA-4 polypeptide, a PD-1 polypeptide, and/or a PD-L1 polypeptide, wherein the bispecific antibody comprises “a heavy chain variable and/or a light chain variable [region] as set forth in any of SEQ ID NOs: 1-12” (which correspond to the VH and VL amino acid sequences set forth above).
These claims do not satisfy the written description requirement because the claims do not completely define all of the structural elements (i.e., amino acid sequences comprising the complementarity determining regions or CDRs) expected to correlate with the instantly claimed function of binding to DR5 and to one of ROCK1, PD-1, PD-L1, or CTLA-4 based on the state of the prior art. Furthermore, the claim language reciting that said bispecific antibody may comprise “any one of SEQ ID NOs: 1-12” includes in its scope “mixing and matching” of one or more of the VH and VL amino acid sequences corresponding to these sequences. Many combinations of said VH or VL domains would not be expected to bind to the same antigen (if any) based on what is known in the prior art, e.g., an antigen-binding domain comprising the VH having SEQ ID NO: 4 (anti-DR5) combined with the VL having SEQ ID NO: 9 (anti-PD-L1) would not be expected to have or retain binding to either of DR5 or PD-L1. Even if only one of a VH or VL is selected, the claim would be drawn broadly to antibodies comprising any possible corresponding VL or VH, respectively, not all of which would be expected to bind one of the recited antigens based on the state of the prior art.
State of the prior art. It is well established in the art that the formation of an intact antigen-binding site in an antibody usually requires the association of the complete heavy and light chain variable regions of a given antibody, each of which comprises three CDRs (or hypervariable regions) that provide the majority of the contact residues for the binding of the antibody to its target epitope. See Almagro (Frontiers in Immunology (2018) 8: 1751), “The IgG Molecule” (page 3) and Figure 1. Sela-Culang (Frontiers in Immunology (2013) 4: 302) further teaches, “A major focus in analyzing the structural basis for [antigen] recognition has been in identifying the exact boundaries of the CDRs in a given [antibody]. It is a common practice to identify paratopes through the identification of CDRs” (page 3).
Although the prior art teaches some understanding of the structural basis of antigen-antibody recognition, it is aptly noted that the art is characterized by a high level of unpredictability, since the skilled artisan still cannot accurately and reliably predict the consequences of amino acid substitutions, insertions, and deletions in the antigen-binding domains. Ni (The Protein Journal (2024) 43: 683-696) teaches, “Mutations, even one mutation, introduced in the CDRs through [somatic hypermutation] can change the binding properties and repertoire of antibodies. However, how just one-point mutation can dramatically change the recognition profiles of the antibody is still unclear” (Introduction). Furthermore, while affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody, those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori (Almagro, pages 3 and 6-7).
Further, the state of the art recognizes that it is not possible to predict the amino acid sequence when an epitope is recited, because there are many different epitope arrangements, such as linear and discontinuous epitopes, that are dictated by the unique interaction between an antibody and its cognate epitope (Blythe, Protein Science (2005) 14:246-248; page 246).
As reviewed by Dubuisson (Antibodies (Basel) (2017) 6(4): 16; supra), many agonistic monoclonal antibodies against DR5 have been developed, including conatumumab (AMG655), drozitumab (Apomab), lexatumumab, LBY135, tigatuzumab (e.g., Section 4; Figure 5), each comprising a complement of VH and VL CDRs that confer their antigen-binding properties. Likewise, immune checkpoint inhibiting antibodies against PD-1 (e.g., nivolumab, pembrolizumab, REGN2810), PD-L1 (e.g., avelumab, atezolizumab, durvalumab), and CTLA-4 (e.g., ipilimumab, tremelimumab), each comprising a complement of VH and VL CDRs that confer their respective antigen-binding specificities, are also well-known in the art. See, e.g., Darvin (Experimental & Molecular Medicine (2018) 50: 165) or Akinleye (Journal of Hematology & Oncology (2019) 12: 92) for review. Monoclonal antibodies against ROCK1 have also been described. See, e.g., Knipe (American Journal of Respiratory Cell and Molecular Biology (2018) 58(4): 471-481), Hu (Molecular Medicine (2020) 26: 124), and Steurer (Aging (2019) 11(18): 7859-7879). Bispecific antibody compositions having dual specificity for DR5 and immune checkpoint proteins (e.g., PD-1, PD-L1, CTLA-4) are disclosed, e.g., by Loew (US 2019/0218311 A1) and Barnhart (US 2016/0067337 A1).
Scope of species disclosed in original specification. The specification describes the generation of one exemplary bispecific antibody “avelu-MD5-1” (Example 7, pages 86-87). Avelu-MD5-1 comprises the anti-PD-L1 antibody avelumab with the murine DR5 agonist MD5-1 antibody (anti-muDR5 scFv), which is conjugated to the C-terminus of each heavy chain Fc of avelumab (e.g., Figures 6E-6F; Example 7). Example 7 discloses that the avelu-MD5-1 bispecific antibody showed binding of and tumor-killing ability against 4T1 and MC38 cells (e.g., Figures 18B, 18C, 18D, 6H, 6I, 6J). Example 7 further discloses that a significantly higher percentage of IFN-γ positive CD8+ cells were observed in avelu-MD5-1-treated tumors (e.g., Figure 25).
The specification discloses that the VH and VL of avelumab comprise the amino acid sequences of SEQ ID NO: 9 and 10, respectively (e.g., pages 16-17; Table 7, pages 94-95). The specification does not disclose the structure (amino acid sequences) of the antigen-binding regions of MD5-1.
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. While one exemplary bispecific antibody construct is described in the disclosure, a single example cannot be said to be broadly representative of all possible bispecific antibodies having dual specificity for DR5 and for one of PD-1, PD-L1, CTLA-4, and ROCK-1.
In the absence of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics; i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. As illustrated by the state of the prior art, the complement of three heavy chain CDRs and three light chain CDRs in the antigen-binding domain of a conventional monoclonal antibody are responsible for conferring its specificity for binding antigen. As set forth above, the specification does not recite the amino acid sequences of the heavy chain or light chain of the murine anti-DR5 antibody MD5-1 or a humanized variant thereof. The amino acid sequences of SEQ ID NO: 1-8 as recited in the claims are stated in the disclosure to correspond to the VH or VL of other anti-DR5 antibodies, specifically lexatumumab (SEQ ID NO: 1-2), tigatuzumab (SEQ ID NO: 3-4), AMG-655 (SEQ ID NO: 5-6), and KMTR2 (SEQ ID NO: 7-8), at pages 94-95. The full complement of a specific combination of VH and VL domains, having demonstrated specificity for a specific antigen, would be necessary to satisfy the written description requirement. The VH region from one anti-DR5 antibody could not be combined with a VL region from another anti-DR5 antibody and be expected, absent experimental validation showing otherwise, to retain binding specificity for DR5. Further, as understood in the art, both the VH and VL (i.e., antigen-binding regions) of avelumab (SEQ ID NO: 9-10) are required to confer its binding specificity for PD-L1. (The VL and VH domains corresponding to SEQ ID NO: 11 and 12 bind to FOLR1, which would not be expected to confer binding to any of DR5, PD-1, PD-L1, CTLA-4, or ROCK1.)
Conclusion. For the reasons presented above, one of skill in the art would not know which of the countless other antibodies encompassed by the highly general structural requirements of the claims would also possess the required functional activity. Given the lack of shared structural properties that provide the claimed binding activity, the limited number of species described, and the fact that the species that were described cannot be considered representative of the broad genus, the Applicant did not possess the full genus of bispecific antibodies as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
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.
Claims 1-14, 16-21, and 23 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Loew (US 2019/0218311 A1; supra) as evidenced by Herold (Scientific Reports (2017) 7: 12276).
Loew discloses bispecific antibody molecules that include a kappa light chain polypeptide and one lambda light chain polypeptide, and methods of making and using the same (e.g., Abstract). Loew teaches that the present invention is based on the unexpected discovery that kappa light chains do not pair with a heavy chain from a lambda antibody and vice versa, thereby overcoming the commonly known problem of light chain mispairing during the manufacture of bispecific antibodies (e.g., ¶ 0002-0004). Regarding claims 13, 16, 20, and 23, Loew discloses in one aspect of the invention a bispecific antibody (“multispecific molecule 6”) which comprises an anti-PD-1 binding arm and an anti-TRAILR2 (also known as DR5) binding arm, wherein the anti-PD-1 arm comprises a first and second chain comprising the amino acid sequences of SEQ ID NO: 181 and 182, respectively, and the anti-TRAILR2 arm comprises a first and a second chain comprising the amino acid sequences of SEQ ID NO: 177 and 148, respectively (e.g., ¶ 0205; Example 7, ¶ 0470-0471; Figure 5; claim 111). In another embodiment, Loew discloses a bispecific antibody (“multispecific molecule 4”) which comprises an anti-CTLA-4 binding arm comprising the amino acid sequences of SEQ ID NO: 168 and 106 and an anti-TRAILR2 binding arm comprising the amino acid sequences of SEQ ID NO: 177 and 148 (¶ 0205, Example 5, ¶ 0466-0467).
Loew further discloses exemplary pairings of kappa and lambda antibodies (Tables 17-18, pages 29-30), including kappa antibodies of nivolumab (anti-PD-1, comprising SEQ ID NO: 409 and 410) or ipilimumab (anti-CTLA-4, comprising SEQ ID NO: 405 and 406) with lambda antibody lexatumumab (anti-TRAILR2, comprising SEQ ID NO: 411 and 412). Regarding claims 14 and 21, the amino acid sequence of SEQ ID NO: 411 (121 amino acid residues in length) shares 100% sequence identity to residues 1-121 of instant SEQ ID NO: 2, and the amino acid sequence of SEQ ID NO: 412 (108 amino acid residues in length) shares 100% sequence identity to residues 1-108 of instant SEQ ID NO: 1. As evidenced by Herold, immunoglobulin VH domains are approximately 125 residues in length and VL domains are about 110 residues in length (page 1). Thus, the exemplary VH and VL domain sequences of lexatumumab as disclosed by Loew read on “a heavy chain variable region” and “a light chain variable [region]” of SEQ ID NO: 1 and 2. (Based on their respective lengths, the amino acid sequence of instant SEQ ID NO: 2 appears to comprise the VH region as well as CH1, CH2, and CH3 domains, and the amino acid sequence of instant SEQ ID NO: 1 appears to comprise the VL region as well as the CL domain.)
Regarding claims 10-12, 16-19, and 23, Loew discloses pharmaceutical compositions comprising the multispecific molecules of the invention and a pharmaceutically acceptable carrier (e.g., ¶ 0181, 0410-0414).
Regarding claims 1-9, Loew discloses methods of treating a subject having cancer, e.g., a solid cancer such as pancreatic cancer, by administering pharmaceutical compositions comprising the multispecific antibody molecules of the invention (e.g., ¶ 0182, 0410-0414).
Claims 1-12, 17, and 19 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Barnhart (US 2016/0067337 A1).
Barnhart discloses methods and compositions for treating cancer using an effective amount of a PD-1 antagonist (e.g., antibody) in combination with a DR5 agonist (e.g., antibody). Barnhart discloses a method of treating cancer, comprising co-administering (1) an agonistic anti-DR5 antibody (e.g., lexatumumab, tigatuzumab, conatumumab, drozitumab, LBY-135) and (2) an antagonistic anti-PD-1 antibody (e.g., nivolumab) or an antagonistic anti-PD-L1 antibody (e.g., MEDI4736, also called durvalumab) (e.g., ¶ 0009-0016, 0029), anticipating claims 1 and 3-8. Regarding claim 2, the cancer is a solid cancer such as pancreatic cancer (e.g., ¶ 0019). Regarding claims 9-10, 12, 17, and 19, Barnhart provides for compositions comprising a PD-1 antagonist and a DR5 agonist, which may be formulated separately or together (e.g., ¶ 0021, 0088-0096).
Relevant to claim 11, Barnhart teaches that the DR5 agonist or the PD-1 antagonist is a bispecific antibody (e.g., ¶ 0011-0012, 0021, 0043, 0085).
Claim Rejections - 35 USC § 103
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 13, 15, 20 and 22 are rejected under 35 U.S.C. 103 over Loew (US 2019/0218311 A1; supra) as evidenced by Herold (Scientific Reports (2017) 7: 12276; supra) as applied to claims 1-14, 16-21, and 23 above, further in view of Morgensztern (Clinical Cancer Research (2016) 22(15): 3713-3717) and as further evidenced by Urosev (US 2019/0338048 A1).
The teachings of Loew are recited in the 35 U.S.C. § 102 rejection above.
However, although Loew teaches that the antibody molecule of the invention can be a humanized antibody (e.g., ¶ 0288, 0304-0311), Loew does not expressly teach an embodiment wherein a bispecific antibody of the invention comprises a humanized DR5-binding domain or a humanized PD-1-binding domain.
Morgensztern reviews the use of nivolumab and pembrolizumab for treating non-small cell lung cancer (NSCLC). Morgensztern teaches that patients treated with anti-PD-1 antibodies nivolumab or pembrolizumab display increased overall survival compared to standard second-line docetaxel, and that the treatments were generally well tolerated and the responses were often durable (e.g., Abstract). Morgansztern notes that nivolumab is a fully human antibody (page 3714) while pembrolizumab is a humanized antibody (page 3715).
As evidenced by Urosev (Table A, pages 13-14), pembrolizumab, like nivolumab, has a kappa light chain.
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to substitute the anti-PD-1 binding domain derived from nivolumab with one derived from pembrolizumab in the anti-DR5/anti-PD-1 bispecific antibody taught by Loew. The skilled artisan would have been motivated to do so because Morgensztern teaches that nivolumab and pembrolizumab both increase overall survival, are well tolerated, and have durable responses in NSCLC patients. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that nivolumab and pembrolizumab are functional equivalents (PD-1 inhibitors) that are useful for the same purpose (treating a solid cancer), and further, both nivolumab and pembrolizumab have a kappa light chain and could efficiently pair with lexatumumab, which has a lambda light chain, based on the teachings of Loew (and also Urosev, e.g., at Abstract, ¶ 0002-0007).
Claims 10-14, 16-21, and 23 are rejected under 35 U.S.C. 103 as being unpatentable over Barnhart (US 2016/0067337 A1; supra) as applied to claims 1-12, 17, and 19 above, and further in view of Loew (US 2019/0218311 A1; supra) as evidenced by Herold (Scientific Reports (2017) 7: 12276; supra) and Urosev (US 2019/0338048 A1; supra).
The teachings of Barnhart are recited in the 35 U.S.C. § 102 rejection above.
However, Barnhart does not expressly recite a bispecific antibody comprising a first antigen-binding site specific for DR5 and a second antigen-binding site specific for PD-1 or PD-L1.
The teachings of Loew and Urosev are described in the rejections under 35 U.S.C. § 102 and 103 above.
In view of the above, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a bispecific antibody comprising an anti-PD-1 binding domain (e.g., derived from nivolumab) and an anti-DR5 (TRAILR2) binding domain (e.g., derived from lexatumumab), or comprising an anti-PD-L1 binding domain (e.g., derived from durvalumab) and an anti-DR5 binding domain (e.g., derived from drozitumab), for use in treating a solid cancer. The skilled artisan would have been motivated to do so because Loew discloses bispecific antibodies having dual specificity for DR5 (TRAILR2) and immune checkpoint proteins including PD-1 for use in treating cancer, and further, Loew teaches that kappa antibody light chains do not pair with lambda antibody heavy chains and vice versa, thereby minimizing the likelihood of light chain mispairing. Further, a bispecific antibody would have the advantage of being easier to administer and provide a more comfortable experience for the patient in need thereof since the active ingredients (the DR5 agonist component and the PD-1 or PD-L1 antagonist component) would be comprised in a single formulation. There would have been a reasonable expectation of success because (1) nivolumab has a kappa light chain while lexatumumab has a lambda light chain (see Loew at Table 18 and Urosev at Tables A and B, pages 13-15), and (2) durvalumab has a kappa light chain while drozitumab has a lambda light chain (see Urosev at Tables A and B, pages 13-15).
Claims 13, 15, 20, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Barnhart (US 2016/0067337 A1; supra) in view of Loew (US 2019/0218311 A1; supra) as evidenced by Herold (Scientific Reports (2017) 7: 12276; supra) and Urosev (US 2019/0338048 A1; supra), as applied to claims 10-14, 16-21, and 23, and further in view of Morgensztern (Clinical Cancer Research (2016) 22(15): 3713-3717; supra).
The teachings of Barnhart are recited in the 35 U.S.C. § 102 rejection above.
However, Barnhart does not expressly recite a humanized bispecific antibody.
The teachings of Loew, Morgensztern, and Urosev are described in the rejections under 35 U.S.C. § 102 and 103 above.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to generate a bispecific antibody comprising an anti-PD-1 binding domain (e.g., derived from pembrolizumab) and an anti-DR5 (TRAILR2) binding domain (e.g., derived from lexatumumab), for use in treating a solid cancer, based on the collective teachings of Barnhart, Loew, and Morgensztern. The skilled artisan would have been motivated to do so because: (1) Loew discloses bispecific antibodies having dual specificity for DR5 (TRAILR2) and immune checkpoint proteins including PD-1 that have utility in treating cancer, and a bispecific antibody formulation, comprising both “active” components within one molecule/formulation, would be easier to administer and provide a more comfortable experience for patients. (2) Further, Morgensztern teaches that nivolumab and pembrolizumab both increase overall survival, are well tolerated, and have durable responses in NSCLC patients, and thus could be used interchangeably. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that nivolumab and pembrolizumab are functional equivalents (PD-1 inhibitors) that are useful for the same purpose (treating a solid cancer), and further, both nivolumab and pembrolizumab have a kappa light chain and could efficiently pair with lexatumumab, which has a lambda light chain, based on the teachings of Loew (and also Urosev, e.g., at Abstract, ¶ 0002-0007).
Conclusion
The prior art made of record and not relied upon is considered pertinent to Applicant's disclosure:
Overdijk (US 2019/0315877 A1) discloses monospecific or bispecific antibodies that specifically bind to human DR5 and methods of use thereof in treating solid cancers (e.g., Abstract, ¶ 0415-0439). Overdijk teaches that anti-DR5 antibodies including lexatumumab, drozitumab, and tigatumumab are generally well-tolerated in clinical studies but that they fail to show “convincing and significant clinical benefit” (¶ 0005). Accordingly, “efforts to enhance the efficacy of DR5 targeting antibodies mainly focus on (i) improving the sensitivity of cancer cells to DR5 agonists through combination treatment, (ii) developing biomarkers for better patient stratification, and (iii) the development of DR5-targeting agents that activate DR5 signaling and apoptosis-induction more effectively” (¶ 0005). Overdijk provides a method of treating cancer that comprises administering an agonistic anti-DR5 antibody of the invention in combination with an additional therapeutic agent, e.g., an anti-PD1 antibody, anti-PD-L1 antibody, or anti-CTLA-4 antibody (e.g., ¶ 0435-0436).
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