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 May 13, 2026 with the Response to the non-final Office Action are acknowledged. Claims 4 and 7 have been canceled. Claims 1-3, 5-6, 8-14, 16-21, and 23 are amended.
Claims 1-3, 5-6, and 8-23 are pending and under examination herein.
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 - The Incorporation by Reference paragraph required by 37 CFR 1.821(c)(1) is defective. Specifically, the Incorporation by Reference Paragraph should list the file size in bytes, not kilobytes.1 See item 1) a) or 1) b) 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.
WITHDRAWN OBJECTIONS AND REJECTIONS
The prior grounds of objection to the specification are withdrawn in view of Applicant's amendments to ¶ 0007, 0197, and 0314.
All prior grounds of rejection over claims 4 and 7 are rendered moot by the cancelation of the claims.
The objection to claims 8, 14, and 21 is withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1-3, 5-6, 8-12, 14, 17-21, and 23 are withdrawn in view of Applicant's claim amendments.
The rejection of claims 14 and 21 under 35 U.S.C. § 112(d) is withdrawn in view of Applicant's amendments to said claims.
The rejection of claims 1-3, 5-6, 8-14, 16-21, and 23 under 35 U.S.C. § 102 as being anticipated by Loew (US 2019/0218311 A1) as evidenced by Herold (Scientific Reports (2017) 7: 12276) is withdrawn in view of Applicant's claim amendments to recite a ROCK1 inhibitor and/or binding domain.
The rejection of claims 13, 15, 20 and 22 under 35 U.S.C. 103 over Loew (US 2019/0218311 A1) as evidenced by Herold (Scientific Reports (2017) 7: 12276), further in view of Morgensztern (Clinical Cancer Research (2016) 22(15): 3713-3717) and as further evidenced by Urosev (US 2019/0338048 A1), is withdrawn in view of Applicant's claim amendments to recite a ROCK1 inhibitor and/or binding domain.
The rejection of claims 10-14, 16-21, and 23 under 35 U.S.C. 103 as being unpatentable over Barnhart (US 2016/0067337 A1) further in view of Loew (US 2019/0218311 A1) as evidenced by Herold (Scientific Reports (2017) 7: 12276) and Urosev (US 2019/0338048 A1) is withdrawn in view of Applicant's claim amendments to recite a ROCK1 inhibitor and/or binding domain.
The rejection of claims 13, 15, 20, and 22 under 35 U.S.C. 103 as being unpatentable over Barnhart (US 2016/0067337 A1) in view of Loew (US 2019/0218311 A1) as evidenced by Herold (Scientific Reports (2017) 7: 12276) and Urosev (US 2019/0338048 A1), further in view of Morgensztern (Clinical Cancer Research (2016) 22(15): 3713-3717), is withdrawn in view of Applicant's claim amendments to recite a ROCK1 inhibitor and/or binding domain.
NEW OBJECTIONS, MAINTAINED REJECTIONS, AND NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENT
Specification
The use of the terms BAVENCIO® (trade name for avelumab), KEYTRUDA® (trade name for pembrolizumab), LIBTAYO® (trade name for cemiplimab), OPDIVO® (trade name for nivolumab), TECENTRIQ® (trade name for atezolizumab), TYVYT® (trade name), and ALEXA FLUOR®, which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the terms 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
Claims 3, 6, and 17 are objected to for the following informalities:
Claims 3 and 17 newly recite “a Cytotoxic T-Lymphocyte Associated Protein 5 (CTLA4) inhibitor” in lines 3-4 and 15, respectively. The claims should instead recite “a Cytotoxic T-Lymphocyte Associated Protein 4 (CTLA4) inhibitor”.
Claim 6 recites “…wherein the checkpoint inhibitor comprises an antibody is selected from the group consisting of…”. It is suggested that this language be amended for clarity.
Appropriate correction is required.
Applicant is advised that should claims 13-15 be found allowable, claims 20-22 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 bispecific antibodies recited in claims 13-15 and in claims 20-22.
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. This is a maintained rejection that has been updated to reflect Applicant's amendments to the claims.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or it may be satisfied by the disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. “Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species. Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). “[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A “representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The “structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For example, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875 (Fed. Cir. 2011).
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 ROCK1 polypeptide, 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: 1-8”. 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), and
SEQ ID NO: 7-8 correspond to the VL and VH of KMTR2 (anti-DR5 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, 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: 1-8” (which correspond to the VH and VL amino acid sequences set forth above).
These claims do not satisfy the written description requirement because the claim language reciting that said bispecific antibody may comprise “any one of SEQ ID NOs: 1-8” includes in its scope “mixing and matching” of one or more of the VH and VL amino acid sequences corresponding to these sequences. While the claimed amino acid sequences correspond to antibodies that bind to DR5, it is understood in the art that the VH from one antibody cannot be paired with the VL of a separate antibody, which may bind to a separate epitope of the same antigen, and consistently result in a functional pairing that binds to the desired cognate antigen. 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. 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). Ma (Frontiers in Immunology (2021) 12: Article 626616) teaches that the clinical therapeutic effects of bispecific antibodies are superior to those of monoclonal antibodies, with broad applications for the treatment of tumors and other diseases (e.g., Abstract). Ma teaches that bispecific antibodies offer flexibility for targeting a combination of antigens (e.g., page 2, left column).
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.
Response to Arguments
Applicant's arguments filed May 13, 2026 have been fully considered but they are not persuasive.
Applicant submits that the 35 U.S.C. § 112(a) written description rejection should be withdrawn in view of Applicant's amendments to claims 14 and 21.
In response, it is held that the amendments do not address the grounds of rejection relating to the “mixing and matching” of one or more mispaired VH and VL amino acid sequences or for a singular VH or VL sequence that could be paired with a structurally undefined counterpart. Accordingly, the rejection is maintained.
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.
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.
(1)
Claims 1, 3, 5-6, 8-10, 17, 19 are rejected under 35 U.S.C. 103 over Peyman (US 2019/0091350 A1) in view of Overdijk (US 2019/0315877 A1; cited in PTO-892 mailed November 2025) and Barnhart (US 2016/0067337 A1; cited in PTO-892 mailed November 2025).
Peyman describes methods using thermotherapy and/or enhanced immunotherapy that comprise the step of administering a plurality of anti-tumor antibody-coated nanoparticles to target a tumor in a patient, wherein the nanoparticles further comprise a medication which is released at the tumor site (e.g., Abstract; ¶ 0035-0060). Pertinent to claims 1, 3, 5-6, 8-10, 17, and 19, Peyman teaches that the nanoparticles of the invention are conjugated with an antibody known in the art and administered along with one or more antibodies, along with a medication that is provided at a much lower dose systemically to kill already comprised tumor cells (e.g., ¶ 0059). The antibodies that may be used (conjugated to or administered along with) include those shown in Table 1 (¶ 0060), e.g., the agonist anti-DR5/TRAIL-R2 antibodies lexatumumab and tigatuzumab and/or the immune checkpoint inhibitors nivolumab (anti-PD-1), durvalumab (anti-PD-L1), and pembrolizumab (anti-PD-1). Peyman discloses that Rock inhibitors such as the ROCK1 inhibitors GSK429286 (“GSK429” as instantly claimed) or GSK269962 (“GSK962” as instantly claimed) may be administered in combination with, conjugated to, or contained as the medication within the nanoparticle compositions of the invention to inhibit inflammatory processes and reduce metastatic spread of tumors (e.g., ¶ 0062-0077, 0129-0135).
However, Peyman does not expressly recite a specific embodiment comprising the combination of an agonist anti-DR5 antibody with an anti-PD-1 antibody or anti-PD-L1 antibody.
Overdijk 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).
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), relevant to claims 1, 3, 5-6, and 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).
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to modify the cancer therapy methods described by Peyman to comprise administering an antibody-coated nanoparticle and a ROCK1 inhibitor (e.g., GSK269962 or GSK429286), wherein the nanoparticle is coated and/or administered along with an anti-DR5 antibody such as lexatumumab and an immune checkpoint inhibitor such as nivolumab or pembrolizumab, based on the further teachings of Overdijk and Barnhart. The skilled artisan would have been motivated to do so because Overdijk teaches that anti-DR5 antibodies generally fail to show clinical benefit on their own and that their efficacy can be enhanced through combination treatment with other agents that improve the sensitivity of cancer cells to DR5, e.g., immune checkpoint inhibitors. There would have been a reasonable expectation of success because Overdijk and Barnhart each provide a proof-of-concept that the use of an agonist anti-DR5 antibody can be paired with an anti-PD-1 antibody (e.g., nivolumab or pembrolizumab) for treatment of solid cancers.
(2)
Claims 13-16 and 20-23 are rejected under 35 U.S.C. 103 over Wajant (Cancers (2019) 11(7): 954) in view of Forero-Torres (Clinical Cancer Research (2018) 21(12): 2722-2729) and Hartmann (Frontiers in Pharmacology (2015) 6: Article 276).
Wajant teaches that DR5 (TRAILR2) triggers cell death in cancer cells and that agonists of DR5 have been developed and tested for their anti-tumor effects (e.g., Abstract). However, Wajant notes that despite promising data from mouse tumor models, clinical studies have failed thus far to show promising anti-tumor efficacy, largely due to acquired TRAIL resistance by tumor cells and a requirement for bivalent anti-TRAIL death receptor antibodies for oligomerization or plasma membrane anchoring to achieve maximal activity (e.g., Abstract). Wajant further teaches, “…bispecific antibodies and antibody fragments recognizing TRAIL death receptors and a second cell surface-exposed target act as strong agonists upon anchoring to the latter (Figure 7). For example, enhanced agonistic activity of anti-TRAILR2 antibodies have been reported for antibody variants with a heavy chain fused with a N- or C-terminal scFv anchoring domain. Vice versa, N-terminal fusion of a TRAILR2-spcecific scFv domain to a MCSP- or FOLR1-specific IgG1 also resulted in increased anchoring-dependent agonism of the scFv-domain. … Bispecific variants of anti-TRAILR2 antibodies with high anchoring-dependent agonism and good in-vivo efficacy have also been generated by the knob-into-hole technology and a CrossFab unit specific for the tumor stroma antigen FAP” (Section 5.2).
While Wajant teaches that bispecific antibody constructs targeting DR5 and a cell surface-exposed target act as strong agonists, Wajant does not expressly teach a bispecific antibody that co-targets ROCK1.
Forero-Torres evaluated the activity of tigatuzumab2 (anti-DR5 agonist antibody) with or without albumin-bound paclitaxel (nab-PAC) in patients with triple-negative breast cancer (TNBC). While objective response rate (ORR) and progression free survival (PFS) were similar in both groups, Forero-Torres noted that gene expression analysis of tumor biopsies from combination treated patients showed that seven genes, four of which are involved in apoptotic membrane blebbing through DR5/Caspase-3/ROCK1 signaling, were significantly associated with response to therapy (Results). Forero-Torres states that the observation that the ROCK pathway is activated by combination treatment with the anti-DR5 agonist merits further evaluation (e.g., Abstract; Discussion).
Hartmann teaches that ROCK1 has been reported to associate with the plasma membrane (e.g., page 2). ROCK1 comprises a C-terminal PH-C1 domain that binds to membrane bilayers via unconventional positively charged surfaces on the domain (e.g., page 2).
In view of these teachings, 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 for use in treating a tumor and/or a cancer (e.g., TNBC), which comprises a first binding site specific for the DR5 polypeptide and a second binding site specific for ROCK1. The skilled artisan would have been motivated to do so because anti-DR5 antibodies exert greater agonist activity when co-targeted with a cell surface-exposed target (as taught by Wajant) and because DR5/Caspase-3/ROCK signaling is implicated in treatment response to an agonist anti-DR5 antibody (as taught by Forero-Torres). There would have been a reasonable expectation of success because it is well within the skill and knowledge of one of ordinary skill in the art at the time of filing of the instantly claimed invention to generate bispecific antibodies, and furthermore, the ROCK1 polypeptide associates with the cell surface (as taught by Hartmann), making it a suitable bispecific antibody co-target based on the teachings of Wajant.
(3)
Claims 17-18 are rejected under 35 U.S.C. 103 over Peyman (US 2019/0091350 A1; supra) in view of Overdijk (US 2019/0315877 A1; supra) and Barnhart (US 2016/0067337 A1; supra) as applied to claims 1, 3, 5-6, 8-10, 17, and 19 above, further in view of Wajant (Cancers (2019) 11(7): 954; supra).
The teachings of Peyman are recited in the 35 U.S.C. § 103 rejection above.
However, Peyman does not expressly teach a composition comprising a bispecific antibody having a first binding site specific for DR5 and a second binding site specific for PD-1 or PD-L1.
The teachings of Overdijk, Barnhart, and Wajant are recited in the 35 U.S.C. § 103 rejections above.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a composition comprising a bispecific antibody that specifically binds to DR5 and to PD-1 or PD-L1. The skilled artisan would have been motivated to do so because monospecific agonist anti-DR5 antibodies have shown limited anti-tumor efficacy in clinical studies (according to Overdijk, Barnhart, and Wajant) and the addition of a targeting domain against a cell surface-attached target increases their activity (according to Wajant). There would have been a reasonable expectation of success because it is well within the skill and knowledge of one of ordinary skill in the art at the time of filing of the instantly claimed invention to generate bispecific antibodies, and furthermore, the PD-1 and PD-L1 polypeptides are each known to be cell surface proteins.
(4)
Claims 13-14 are rejected under 35 U.S.C. 103 over Peyman (US 2019/0091350 A1; supra) in view of Overdijk (US 2019/0315877 A1; supra) and Barnhart (US 2016/0067337 A1; supra) as applied to claims 1, 3, 5-6, 8-10, 17, and 19 above, further in view of Wajant (Cancers (2019) 11(7): 954; supra), Forero-Torres (Clinical Cancer Research (2018) 21(12): 2722-2729) and Hartmann (Frontiers in Pharmacology (2015) 6: Article 276).
The teachings of Peyman are recited in the 35 U.S.C. § 103 rejection above.
However, Peyman does not expressly teach a composition comprising a bispecific antibody having a first binding site specific for DR5 and a second binding site specific for ROCK1 polypeptide.
The teachings of Overdijk, Barnhart, Wajant, Forero-Torres, and Hartmann are recited in the 35 U.S.C. § 103 rejections above.
Taken together, it would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to arrive at a composition comprising a bispecific antibody that specifically binds to DR5 and to ROCK1 polypeptide. The skilled artisan would have been motivated to do so because monospecific agonist anti-DR5 antibodies have shown limited anti-tumor efficacy in clinical studies (according to Overdijk, Barnhart, and Wajant) and the addition of a targeting domain against a cell surface-attached target increases their activity (according to Wajant). There would have been a reasonable expectation of success because it is well within the skill and knowledge of one of ordinary skill in the art at the time of filing of the instantly claimed invention to generate bispecific antibodies, and furthermore, the ROCK1 polypeptide associates with the cell surface (as taught by Hartmann), making it a suitable bispecific antibody co-target based on the teachings of Wajant.
Conclusion
No claims are allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/Brad Duffy/Primary Examiner, Art Unit 1643
1 It is noted that this requirement applies regardless of whether the sequence listing is filed under ST.25 or ST.26.
2 As evidenced by the instant specification (e.g., Table 7 at pages 94-95), tigatuzumab comprises a VL having the amino acid sequence of SEQ ID NO: 3 and a VH having the amino acid sequence of SEQ ID NO: 4 (pertinent to claims 14 and 21) and is a humanized antibody (pertinent to claims 15 and 22).
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