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 March 2, 2026 are acknowledged. Claim 9 has been amended. Claims 1-34 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.
Priority
The present application claims the benefit of U.S. Patent Application No. 17/499,012.
The earliest support for claims 1-8, 10-12, and 15-34 is found in the U.S. Provisional Patent Application No. 63/008,988 filed April 13, 2020.
The earliest support for the subject matter recited in claim 9, is found in U.S. Patent Application No. 17/499,012 filed October 12, 2021.
The earliest support for the subject matter recited in claims 13-14, is found in the PCT/US2022/077889 application filed October 11, 2022.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code throughout the disclosure. See, for example, Examples 1 and 2 (pages 47-48) and References (pages 106-121). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is further objected to for the following informalities:
The description for Figure 5 (page 5) states that human “IGHV2-23*04” was used as the humanization backbone for the heavy chain and that human “IGKV2-39*01” was used as the humanization backbone for the light chain of the antibody construct originally set forth by Du (Supplementary Figure 2). However, the figure itself states that “IGHV3-23*04” was used for the heavy chain and that “IGKV1-39*01” was used for the light chain.
The description for Figure 6 (pages 4-5) recites that the light chain sequence of SEQ ID NO: 76, illustrated in the drawing, comprises residues 21-230, “beginning with DIQ… and ending with …GEC”. However, according to the CRF Sequence Listing and the Drawing, the full sequence is 233 residues and residues 228-230 correspond to “FNR”, not “GEC”.
The descriptions for Figures 7 and 8 (page 5) recite that the heavy chains of SEQ ID NO: 77 and 78 comprise “residues 25-471, beginning with EVQ… and ending with …SPG”. However, according to the CRF Sequence Listing and the Drawings, each of the heavy chains corresponding to SEQ ID NO: 77 and 78 contain 473 amino acid residues, and residues 469-471 in each of these sequences corresponds to “SLS”, not “SPG.”
Appropriate clarification and/or correction is requested.
Claim Interpretation
For the purposes of establishing the broadest reasonable interpretation of the instant claims, in particular the relative terminology describing the functional properties of the monoclonal antibody recited in claim 1, the Applicant’s broad definitions provided in the specification are relied upon herein:
As defined in the specification (pages 16-17), a monoclonal antibody “specifically binds” to the extracellular portion of hACE2 if it (i) binds to the extracellular portion of hACE2 with an affinity greater than that with which it binds to any other human cell surface protein, or (ii) binds to the extracellular portion of hACE2 with an affinity of at least 500 µm.
As defined in the specification (page 17), a monoclonal antibody “specifically inhibits binding of SARS-CoV-2 to the extracellular portion of hACE2” if it (i) reduces the binding of SARS-CoV-2 to hACE2 more than it reduces the binding of SARS-CoV-2 to any other human cell surface protein, or (ii) reduces the binding of SARS-CoV-2 to hACE2 by a factor of at least two.
As defined in the specification (pages 15-16), “a monoclonal antibody does not ‘significantly inhibit the ability of hACE2 to cleave’ a substrate if (i) it inhibits the ability of intact hACE2 (i.e., full-length hACE2 that includes the extracellular portion, transmembrane portion, and intracellular portion) to cleave the substrate by less than 90%, and/or (ii) it inhibits the ability of the extracellular portion of hACE2 (e.g., recombinant soluble hACE2) to cleave the substrate by less than 90%.” For example, as recited on pages 15-16, the monoclonal antibody does not significantly inhibit the ability of hACE2 (i.e., intact hACE2 and/or its extracellular portion) to cleave angiotensin II or a synthetic MCA-based peptide (preferably Mca-APK(Dnp)) if it inhibits that ability by less than 90%, less than 80%, less than 70%, less than 60%, less than 50%, less than 40%, less than 30%, less than 20%, less than 10%, less than 5%, or less than 1 %.
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 13-14 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second
paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 13 is indefinite because the claim recites Figures 6 and 7, and claim 14 is indefinite because the claim recites Figures 6 and 8. MPEP § 2173.05(s) states: “Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table “is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience.” Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted). In this case, the sequences that the figures refer to (i.e., SEQ ID NO: 76, 77, and 78) could easily be incorporated in to the claim to define the invention.
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 1-8 and 10-34 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).
Amgen Inc. v. Sanofi, Aventisub LLC, 872 F.3d 1367 (Fed. Cir. 2017) supported previous decisions (Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341 (Fed. Cir. 2011); AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285 (Fed. Cir. 2014)) that defining an antibody solely by what it binds does not satisfy the written description requirement, stating that this would allow patentees to “claim antibodies by describing something that is not the invention, i.e., the antigen”. Thus, claiming an antibody by describing the invention by what it does (function) rather than what it is (structure) is invalid. This can be overcome if a relevant number of species with structure/function correlation is known to the art or present in the specification.
The claimed invention. The nature and scope of the claimed invention at issue is a monoclonal antibody (mAb) that specifically binds to the extracellular portion of human angiotensin converting enzyme 2 (hACE2), inhibits binding of SARS-CoV2 to the extracellular portion of hACE2, and does not significantly inhibit the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based synthetic peptide (as recited in claim 1 and the dependent claims). The claims further recite that the mAb does not specifically bind to an epitope on hACE2 comprising an amino acid residue as recited in claims 4-6 and does bind an epitope on hACE2 comprising one of the amino acid residues recited in claims 7-8.
These claims fail to satisfy the written description requirement because they define the instantly claimed monoclonal antibody by its functional attributes (i.e., specifically binding to a specific epitope of hACE2; inhibiting binding of SARS-CoV-2 to the extracellular portion of hACE2; and not significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide) without reciting a corresponding structure that would be expected to correlate with these claimed functions based on the teachings of the prior art and in light of Applicant's disclosure. A person of ordinary skill in the art would be unable to visualize or recognize the members of the broad genus of antibodies having these functional characteristics a priori.
Of note, claim 9 recites a sufficient level of structure (i.e., three heavy chain CDRs and three light chain CDRs that are fully defined by sequence) such that the recited antibody would be expected to possess the instantly claimed functional properties based on the teachings of Du (Nature Communications (2021) 12: 5000; cited in IDS). The “11B11” antibody taught by Du, which comprises the instantly claimed combination of heavy chain and light chain CDRs recited in claim 9, binds an epitope of hACE2 on the N-terminal helix (NTH), which comprises the extracellular domain (page 7, left column; Figure 5), blocks binding of the SARS-CoV-2 receptor-binding domain (RBD) to hACE2 (page 2, right column; Figure 1a; page 7, left column; Figure 5), and does not significantly inhibit the ability of hACE2 to cleave angiotensin II (pages 2-3; Figure 1d).
It is also noted that while claim 11 is drawn to a human monoclonal antibody, the antibody recited by Du and disclosed in Figure 5 of the application has murine CDRs, not human CDRs. A murine antibody is derived from mouse sequences, whereas a human antibody is derived from a human source and does not contain any murine sequences. See, e.g., Harding (MAbs (2010) 2(3): 256-265) at page 258. Harding teaches that murine sequences are immunogenic to humans, and murine-derived CDRs can be engrafted into human sequence-derived framework regions to produce humanized antibodies (page 258).
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) at pages 3 or 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, left column, “CDRs Identification”).
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).
Gershoni (Biodrugs (2007) 21(3): 145-156) teaches that antibody binding to the same antigen, or even the same epitope on that antigen, can be accomplished with an impressively wide variety of antibody structures, even when the antibodies are limited to those from a particular source (page 146, Section 1.1). The skilled artisan therefore understands that antibodies from a variety of different sources may bind the same antigen and even mediate the same functional effects, but differ widely in the details of the structure of their antigen-binding sites, particularly in the amino acid sequence. Furthermore, 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. See, e.g., Blythe (Protein Science (2005) 14:246-248) at page 246.
Exemplary antibodies that specifically bind human ACE2 are known in the art, such as those disclosed by Sato (US 2021/0355194 A1), Du (Nature Communications (2021) 12: 5000; cited in IDS), and Ostrov (WO 2021/207213 A2; cited in IDS).
Scope of species disclosed in original specification. The Examples recite various methods for determining the functionality of an anti-hACE2 antibody, e.g., measuring the degree to which an antibody inhibits the ability of hACE2 to cleave angiotensin II (Examples 1-4) or the ability of a monoclonal antibody of the invention to bind to the extracellular portion of hACE2, inhibit binding of SARS-CoV-2 to hACE2, or neutralize virus (e.g., Examples 5-6, wherein the methods of Example 6 are “taken from Du, et al”).
Examples 9-10 describe the purification and ACE2 affinity analysis of four antibodies, “H11B11-hIgG1(STR)”, “H11B11-hIgG1(STR/YTE)”, “3E8-hIgG1(STR)”, and “3E8-hIgG1(STR/LS)”. See also Figures 7-8. The “H11B11” antibody is originally described by Du (supra) (e.g., Figure 5), and the “3E8” antibody is originally described by F. Zhang (e.g., specification at pages 43-44; bioRxiv preprint cited in IDS). Example 11 teaches that the H11B11-hIgG1(STR) and H11B11-hIgG1(STR/YTE) antibodies had abrogated binding to FcRγ, but not FcRn. Example 12 states that the H11B11-hIgG1(STR) and H11B11-hIgG1(STR/YTE) antibodies inhibited binding of ACE2 to all tested spike and RBD constructs and potently bound ACE2. Example 12 also states that the 3E8 antibodies did not inhibit ACE2 binding to SARS-CoV-2 spike or RBD protein constructs (data not shown), but did bind to ACE2.
As recited above, Du (supra) also provides a showing that the “11B11” anti-hACE2 antibody comprising heavy chain CDRs as set forth in instant SEQ ID NO: 2-4, respectively, and light chain CDRs as set forth in instant SEQ ID NO: 5-7, respectively, possesses the instantly claimed functional attributes (e.g., Figures 1 and 5).
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. However, the disclosure appears to only recite a single species of anti-hACE2 antibody (which was originally disclosed by Du) having the instantly claimed functional properties set forth in claim 1. The state of the art illustrates that a wide variety of antibodies differing considerably in their structures (i.e., amino acid sequences) can bind to an antigen or even within a particular epitope on that antigen. Therefore, the disclosure of a single species is not sufficient written description for a claim to a broad genus of antibodies having the specific functional properties set forth in claim 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. Based on the teachings of Du (supra) and the instant specification (e.g., Examples 9-12), only an antibody having the combination of heavy chain CDRs as set forth in instant SEQ ID NO: 2-4, respectively, and light chain CDRs as set forth in instant SEQ ID NO: 5-7, respectively, would be expected to possess the functional attributes described in the claims.
Conclusion. For all of 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 activities. 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 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.
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.
As noted above, claim 9 has a priority date of October 12, 2021.
Claim 9 is rejected under 35 U.S.C. 102(a)(1) as being anticipated by Du (Nature Communications (2021) 12: 5000; published August 17, 2021; cited in IDS).
Du describes the isolation and humanization of an angiotensin-converting enzyme-2 (ACE2)-blocking monoclonal antibody, “h11B11”, which has potent inhibitory activity against SARS-CoV and circulating global SARS-CoV-2 lineages (Abstract). The antibody was generated by immunizing BALB/c mice with hACE2(19-615) soluble antigens in a prime-boost immunization regiment, and the resulting murine 11B11 antibody was humanized through CDR grafting onto human acceptor germline frameworks to minimize immunogenicity, antibody-dependent cellular phagocytosis, and antibody-dependent cell cytotoxicity (Results, page 2).
As previously set forth in the 35 U.S.C. § 112(a) rejection above, the “11B11” antibody possesses the functional properties recited in claim 1. Du teaches that the humanized (h)11B11 antibody has a VH comprising an HCDR1 having the amino acid sequence of “GFTFIDYYMN”, an HCDR2 having the amino acid sequence of “FIRNKANDYTTEYST”, and an HCDR3 having the amino acid sequence of “RHMYDDGFDF” (Supplementary Figure 2a), and a VL comprising an LCDR1 having the amino acid sequence of “ASSSVRYMH”, an LCDR2 having the amino acid sequence of “LLIYDTSKLA”, and an LCDR3 having the amino acid sequence of “QQWSYNPLTF” (Supplementary Figure 2b), all of which share 100% sequence identity to the instantly claimed HCDRs (comprising SEQ ID NO: 2-4, respectively) and LCDRs (comprising SEQ ID NO: 5-7, respectively).
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.
(1)
Claims 1-8, 10-12, 17-22, and 32-33 are rejected under 35 U.S.C. 103 as being unpatentable over Ostrov (WO 2021/207213 A2; earliest priority date: April 7, 2020; cited in IDS) in view of Loibner (U.S. Patent No. 8,241,864; published August 14, 2012; cited in IDS), and as evidenced by Du (Nature Communications (2021) 12: 5000; cited in IDS; supra) and Zhang (bioRxiv (2022) doi: 10.1101/2022.08.24.505169; cited in IDS).
Ostrov discloses compounds and pharmaceutical compositions for use in treating coronavirus infection from SARS-CoV-2 (e.g., COVID-19) (e.g., ¶ 7). Regarding claims 1 and 12, Ostrov recites antibodies and epitope-binding fragments thereof that bind to human ACE2 and inhibit the binding of SARS-CoV-2 to ACE2 (e.g., ¶ 13, 19, 71-72). Relevant to claims 4-8, Ostrov discloses that the anti-hACE2 monoclonal antibodies bind to one or more amino acids in the region of amino acid residues 31-42 of ACE2 (e.g., ¶ 19, 118-120, 198-199; Figure 1). Ostrov teaches that the region of interaction between the SARS-CoV-2 spike protein and ACE2 appears to correspond to amino acid residues 492-503 of the SARS-CoV-2 spike protein and amino acid residues 31-42 of ACE2 (e.g., ¶ 118; Figure 1).
Relevant to claim 10, the antibodies can be humanized (e.g., ¶ 121). Regarding claim 11, Ostrav teaches a method of generating antibodies that inhibit binding of SARS-CoV-2 from binding to ACE2, comprising injecting into a host animal an ACE2 peptide, identifying antibody-producing cells from the injected host animal, and forming hybridoma cells using the antibody-producing cells (¶ 122). A suitable host animal known in the art is a human or a cell derived therefrom, and generating a human antibody would be an obvious variation to humanized or chimeric antibodies as known to those of skill in the art. Known work in one field of endeavor may prompt variations of it for use in the same field provided the variations are predictable to one of ordinary skill in the art. See MPEP § 2143. A human antibody, comprising human-derived sequences, would be expected to be less immunogenic to a human patient subsequently administered the antibody than, e.g., a murine antibody, which is advantageous during a method of treatment.
Relevant to claim 17, Ostrov discloses pharmaceutical compositions comprising antibodies of the invention and pharmaceutically acceptable carriers (e.g., ¶ 80-82).
Relevant to claims 18-22, Ostrov discloses treatment methods that comprise administering an anti-ACE2 antibody of the invention to a subject who is suffering from COVID-19, is susceptible to COVID-19, or has had known or suspected exposure to SARS-CoV-2 virus (e.g., ¶ 7-15, 19, 57-58, 128-140; claims 1-3, 19-21). Ostrov notes that “treating” and “treatment” can refer to a prophylactic effect or to a therapeutic effect that mitigates one or more symptoms (e.g., ¶ 58). Although Ostrov does not expressly state that the antibody of the invention is administered to an asymptomatic subject (relevant to claim 22), Ostrov does state that the antibodies of the invention are administered to those having known or suspected exposure to SARS-COV-2, and it is understood in the art that these individuals would not immediately be symptomatic for an associated disease caused by the virus.
Regarding claims 32-33, Ostrov discloses kits comprising a compound or pharmaceutical composition comprising an antibody of the invention, which can be formulated as a solid formulation (lyophilized) or as a suspension, in combination with a diluent (e.g., ¶ 80, 93-96).
However, Ostrov does not expressly disclose that the anti-hACE2 antibodies of the invention do not significantly inhibit the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide.
Loibner discloses a monoclonal antibody (“enzyme-binding unit”) that specifically binds to the extracellular portion of hACE2 and do not (or to a small extent) influence ACE2 activity, i.e., does not significantly inhibit the ability of hACE2 to cleave angiotensin II, i.e., does not significantly inhibit the ability to cleave a synthetic MCA-based peptide (col 3, line 55 to col 4, line 8; col 4, line 58 to col 5, line 18; claims 1 and 19-20), relevant to claims 1-3. Loibner recites, “With particular enzymes, activity losses caused by the antibody binding cannot be avoided. Here, known selection methods (e.g. phage-display methods) however allow for this inhibition to be kept little” (col 4, lines 61-63). The ACE2 binding units disclosed by Loibner are antibodies, antibody fragments, or single chain antibodies (col 4, lines 43-48), relevant to claim 12.
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to optimize for an anti-hACE2 mAb that specifically binds to the extracellular domain of hACE2, specifically inhibits the binding of SARS-CoV-2 to the extracellular portion of hACE2, and does not significantly inhibit the ability of hACE2 to cleave angiotensin II, and to administer such an antibody in a prophylactic or treatment method. The skilled artisan would have been motivated to do so because such an antibody would have utility in treating a SARS-CoV-2 infection (i.e., preventing the virus from binding to host cells) while allowing the host ACE2 to retain normal or mostly normal function. There would have been a reasonable expectation of success because known selection methods in the art allow for enzyme activity losses caused by antibody binding to be kept minimal (as taught by Loibner).
Furthermore, as also evidenced by Du, the antibody “11B11” provides a clear teaching of an exemplary monoclonal antibody that inherently possesses the instantly claimed functional properties of (i) specifically binding to the extracellular portion of hACE2, (ii) specifically inhibiting binding of SARS-CoV-2 to the extracellular portion of hACE2, and (iii) not significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide. See teachings recited in rejections under 35 U.S.C. §§ 112(a) and 102 above. As further evidenced by Zhang, the 11B11 antibody of Du binds to residue L31 of the hACE2 protein among others (e.g., Figure S3G). This exemplary antibody provides evidence as to why it would be obvious for a monoclonal antibody such as that presently claimed to possess these same functional properties.
(2)
Claims 1 and 15-16 are rejected under 35 U.S.C. 103 as being unpatentable over Ostrov (WO 2021/207213 A1; supra) in view of Loibner (U.S. Patent No. 8,241,864; supra) as further evidenced by Du (Nature Communications (2021) 12: 5000; supra) and Zhang (bioRxiv (2022) doi: 10.1101/2022.08.24.505169; cited in IDS) as applied to claims 1-8, 10-12, 17-22, and 32-33 above, further in view of Verma (Journal of Immunological Methods (1998) 165-181).
The teachings of Ostrov are recited in the 35 U.S.C. § 103 rejection above.
However, Ostrov does not appear to teach an isolated nucleic acid encoding the monoclonal antibody of the invention nor a recombinant vector comprising said nucleic acid.
The teachings of Loibner, Du, and Zhang are discussed above.
Verma reviews expression systems using to engineer antibodies and their fragments. Verma teaches that recombinant antibodies have been produced in bacterial, mammalian, insect, yeast, and other expression systems (page 3, Section 3). Verma describes the process of gene expression using Escherichia coli cells, wherein the gene encoding the antibody molecule is placed in the context of appropriate sequences that allow transcription and translation of the protein (page 167, Section 4). The T7 RNA promoter is one commonly used promoter that Verma teaches can be used to obtain tightly controlled, high level expression (page 167). Advantages of using E. coli expression systems is that this system produces protein in large quantities in a shorter amount of time due to the quick rate of replication in E. coli, and transformation of E. coli with foreign DNA is easy and requires minimal amounts of DNA (page 167). Per Verma, yeast has also been used as an expression vector for whole antibodies and antibody fragments (page 171, Section 5). Two vectors (episomal vectors and integrating vectors) are used in yeast (page 1712, Section 5).
It would have been obvious to one of ordinary skill in the art, before the filing date of the instantly claimed invention, to possess an isolated nucleic acid encoding an anti-hACE2 antibody and a recombinant vector comprising said nucleic acid. The skilled artisan would have been motivated to do so because antibody engineering techniques using expression systems that generate protein antibody proteins from genes (nucleic acids) encoding the antibody, in combination with a vector, can quickly and easily produce large amounts of a desired antibody. There would have been a reasonable expectation of success because the use of gene expression systems to engineer antibodies is well within the technical skill of one of ordinary skill in the relevant art.
(3)
Claims 1, 23-31, and 34 are rejected under 35 U.S.C. 103 as being unpatentable over Ostrov (WO 2021/207213 A1; supra) in view of Loibner (US 8,241,864 B2; supra) as evidenced by Du (Nature Communications (2021) 12: 5000; supra) and Zhang (bioRxiv (2022) doi: 10.1101/2022.08.24.505169; cited in IDS), as applied to claims 1-8, 10-12, 17-22, and 32-33 above, further in view of Hauswirth (US 2018/0057840 A1) and Hamming (The Journal of Pathology (2004) 203: 631-637).
The teachings of Ostrov are recited in the 35 U.S.C. § 103 rejection above.
However, Ostrov does not teach a recombinant AAV particle comprising a nucleic acid sequence encoding an anti-ACE2 monoclonal antibody of the invention or methods of administering such a recombinant AAV for treatment or prophylaxis of a human subject infected with SARS-CoV-2.
The teachings of Loibner, Du, and Zhang are discussed above.
Hauswirth discloses capsid-modified recombinant (r)AAV expression vectors, and compositions comprising the same, that have utility as delivery agents for treating or ameliorating diseases of the mammalian vascular system (e.g., Abstract). Hauswirth teaches that AAV is attractive as a delivery system due to its low immunogenicity in mammalian hosts and ability to effectively transduce non-dividing cells (e.g., ¶ 0005-0007), and that many of the rAAV constructs of the invention are resistant to proteasomal degradation (e.g., ¶ 0033). Hauswirth teaches that the rAAV-based expression systems of the invention encode a promoter (e.g., a vascular endothelial cell (VEC)-specific promoter) and a therapeutic molecule (e.g., an antibody), and are capable of effectively driving transgene expression said therapeutic molecules in mammalian vascular endothelial cells (VECs) (e.g., ¶ 0011-0037), relevant to claims 23-26. Relevant to claims 27-31, Hauswirth further teaches that the rAAV constructs of the invention can be administered to mammalian subjects to treat one or more symptoms of a disease (e.g., ¶ 0011-0013, 0028-0029, 0083-0089). Relevant to claim 34, Hauswirth discloses therapeutic kits comprising a rAAV vector composition of the invention (e.g., ¶ 0032, 0108; claim 26).
Hamming discusses the tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. Hamming teaches that ACE2 is expressed in the vascular endothelium (e.g., Abstract; Results/figures; Discussion).
Based on the further teachings of Hauswirth and Hamming, 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 methods collectively taught by Ostrov and Loibner by administering to the subject in need thereof a recombinant AAV vector comprising a nucleic acid encoding the anti-ACE2 antibody of the invention in order to treat or reduce the likelihood of infection with SARS-CoV-2. The skilled artisan would have been motivated to do so because Hauswirth teaches that rAAVs have utility in treating disease and have several advantages as therapeutic delivery systems (e.g., reduced immunogenicity, resistance to proteasomal degradation). There would have been a reasonable expectation of success because the rAAV constructs described by Hauswirth target VECs, and ACE2 is known to be expressed in VECs as shown by Hamming. Therefore, the rAAV construct encoding an anti-ACE2 antibody (such as that taught by Ostrov and Loibner) would effectively be targeted to the ACE2-expressing cells that are vulnerable to SARS-CoV-2 infection.
(4)
Claims 9 and 13-14 are rejected under 35 U.S.C. 103 as being unpatentable over Yan (CN 114805570 A; earliest priority date: January 27, 2021; published July 29, 2022; machine and original translations attached) in view of Lazar (US 2015/0071948 A1), Hale (WO 2021/234402 A2; earliest priority date: May 21, 2020), and Shitara (U.S. Patent No 8,883,981; published November 11, 2014), and as evidenced by Du (Nature Communications (2021) 12: 5000; supra).
Yan discloses a murine anti-human ACE2 monoclonal antibody, named 11B11, comprising a heavy chain set forth in SEQ ID NO: 11 and a light chain set forth in SEQ ID NO: 12, each comprising the instantly claimed heavy chain and light chain CDR amino acid sequences set forth in claim 9. Said antibody blocks the combination of SARS-CoV-2 RBD and a human ACE2 receptor and inhibits SARS-CoV-2 from infecting a host (e.g., Abstract; ¶ 0007-0018 of machine translation). Yan teaches that in the process of humanizing the mouse 11B11, the variable region sequences were fused with human IgG4 Fc regions (e.g., ¶ 0072 of machine translation). The light chain comprising SEQ ID NO: 12 shares 100% sequence identity to residues 21-230 of the light chain set forth in Figure 6 (SEQ ID NO: 76) as recited in claims 13-14.
As evidenced by Du and reiterated in the rejections above, the 11B11 antibody by virtue of its specific structure inherently possesses the instantly claimed functional properties of (i) specifically binding to the extracellular portion of hACE2, (ii) specifically inhibiting binding of SARS-CoV-2 to the extracellular portion of hACE2, and (iii) not significantly inhibiting the ability of hACE2 to cleave angiotensin II and/or a synthetic MCA-based peptide.
However, Yan does not teach an embodiment of the anti-ACE2 monoclonal antibody wherein the heavy chain is an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in Figure 7 and claim 13) or residues 25-471 of SEQ ID NO: 78 (as set forth in Figure 8 and claim 14).
Lazar discloses IgG Fc variants and polypeptides with optimized effector function (e.g., Abstract; ¶ 0011-0017). In aspects of the invention, the variants include isotypic substitutions such as C131S, R133K, and others (e.g., ¶ 0017-0019). Lazar teaches, “The different IgG isotypes offer a variety of unique physical, biological, and therapeutic properties. For example there are significant differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization state among the isotypes IgG1, IgG2, IgG3, and IgG4. These differences must be due to one or more of the isotypic differences between the IgGs shown in FIG. 1. For example, because the binding site for FcγRs resides on the Fc region, it is likely that the IgG differences in Fc, and even more likely the lower hinge and the CH2 domain, are responsible for the differences in their FcγR-mediated effector functions” (¶ 0591). In an embodiment of the invention, Lazar teaches an IgG4 variant comprising the amino acid substitutions of 234S, 235T, and 236R (e.g., ¶ 0069-0071), relevant to claims 13-14.
Hale also describes proteins comprising variant IgG Fc regions which exhibit modified effector functions (e.g., Abstract). Hale teaches, “In many situations it is desirable to reduce, or preferably eliminate, the binding of IgG to Fcγ receptors, since the biological effects they mediate are unwanted, and may be harmful (e.g. see: Wang 2018). For example, when antibodies are being used to neutralize the activity of an antigen, concomitant activation of cellular responses may be undesirable. However, the Fc region has other useful properties, not least its ability to provide a long half-life by virtue of binding to FcRn. This feature is used in the development of fusion proteins where the Fc region imparts an extended half-life to other bioactive proteins” (page 16). In one embodiment of the invention, Hale describes an optimized Fc variant comprising the substitutions “L234S/L235T/G236R”, which has reduced binding to FcγR but retains binding to FcRn (e.g., pages 24-27, 35-43, 77-79), relevant to claims 13-14. Hale discloses, “Surprisingly, a peptide having only the amino acid substitution G236R was found to have an increased risk of immunogenicity compared with the corresponding wild-type peptide, whereas the addition of additional substitutions at positions 234 and 235 decreased this risk to no more than that of the corresponding wild-type peptide” (pages 30-31).
Hale further notes additional amino acid residues involved in FcRn binding include M252, S254, and T256 (e.g., pages 43-44). Hale teaches that the M252Y/S254T/T256E substitution, among others, increases binding to FcRn at acidic pH and increases serum half-life (e.g., page 44), relevant to claim 14.
Hale additionally notes that human IgG4 has a tendency to form heterodimers with serum IgG4 (i.e., Fab-arm exchange) and that several modifications can be made to IgG4 to minimize this phenomenon (e.g., S228P, C131X, etc.) (e.g., pages 44-45).
Shitara illustrates a sequence alignment of human IgG1, IgG2, IgG3, and IgG4 sequences (Figure 1, reproduced and annotated below). It is noted that residues annotated with a plain arrow on top (corresponding to residues 131, 133, 137-138, etc. according to EU numbering) are those in which IgG1 comprises a different residue at that position than does IgG4, and that the heavy chain sequences of instant SEQ ID NO: 77 and 78 comprise the IgG1-associated residues in at least these positions. These substitutions are consistent with the isotypic substitutions taught by Lazar. The heavy chain taught by Yan comprises an IgG4 hinge, while instant SEQ ID NO: 77 and 78 comprise an IgG1 hinge sequence.
The locations corresponding to the substitutions of residues 234-236 and 252, 254, and 256 according to EU numbering are annotated with dotted arrows above the alignments.
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In view of the teachings above, 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 an anti-ACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76, through a process of routine optimization. The skilled artisan would have been motivated to use an IgG1 heavy chain in place of an IgG4 heavy chain, or to otherwise incorporate IgG1 isotypic substitutions (as provided by Lazar) into the IgG4 heavy chain used by Yan, because (1) Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states, which affect their therapeutic properties, and (2) Hale further teaches that IgG4 antibodies are susceptible to Fab-arm exchange. Thus, the skilled artisan would be motivated to optimize for desired qualities either by adding isotypic substitutions into an IgG4 heavy chain and/or substituting between IgG isotypes. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
The skilled artisan would further have been motivated to substitute the residues “STR” at positions 234-236 because Hale teaches that this modification reduces FcγR binding while retaining FcRn binding (which improves serum half-life), as well as the substitutions of M252Y/S254T/T256E, as Hale teaches that these modifications also improve serum half-life. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
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.
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(1)
Claims 1-10, 15-22, and 32-33 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims anticipate the instantly claimed invention.
Regarding claims 1-4 and 9-10, co-pending claims 1-3 recite a humanized monoclonal antibody having the same functional properties and an identical heavy chain and light chain CDR structure (amino acid sequences) as the instantly claimed monoclonal antibody. Co-pending claims 4-6 teach that the antibody of the co-pending claims does not bind to the same specific residues on hACE2 as recited in claim 4, or to residues 290-307 and 417-430 as recited in claim 5, or to residues 103-289, 398-416, and 431-615 as recited in claim 6. Co-pending claim 7 recites that the antibody does bind to an epitope selected from the same residues as those recited in claims 7-8.
Regarding claims 15-16, co-pending claims 13-14 recite an isolated nucleic acid encoding the light chain and/or heavy chain of the monoclonal antibody and a recombinant vector comprising the same. Regarding claim 17, co-pending claim 15 recites a pharmaceutical composition comprising the monoclonal antibody.
Regarding claims 18-22, co-pending claims 16-20 recite methods with a materially identical step of administering the monoclonal antibody of co-pending claim 1.
Regarding claims 32-33, co-pending claims 30-31 recite kits comprising materially identical components as those instantly claimed.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(2)
Claims 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application) as applied to claims 1-10, 15-22, and 32-33 above, further in view of Lazar (US 2015/0071948 A1; supra), Hale (WO 2021/234402 A2; supra), and Shitara (U.S. Patent No 8,883,981; supra).
The teachings of the co-pending reference application are discussed in the non-statutory double patenting rejection above.
However, the co-pending claims do not recite that the monoclonal antibody comprises an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in Figure 7 and claim 13) or residues 25-471 of SEQ ID NO: 78 (as set forth in Figure 8 and claim 14).
The teachings of Lazar, Hale, and Shitara are discussed in the 35 U.S.C. § 103 rejection above.
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 an anti-ACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76, through a process of routine optimization. The skilled artisan would have been motivated to use an isotypically IgG1 heavy chain because Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states. These differences affect their therapeutic properties and can be optimized for desired qualities. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
The skilled artisan would further have been motivated to substitute the residues “STR” at positions 234-236 because Hale teaches that this modification reduces FcγR binding while retaining FcRn binding (which improves serum half-life), as well as the substitutions of M252Y/S254T/T256E, as Hale teaches that these modifications also improve serum half-life. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(3)
Claims 1, 23-31, and 34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 13-20, and 30-31 of co-pending Application No. 17/499,012 (reference application) as applied to claims 1-10, 15-22, and 32-33 above, further in view of Hauswirth (US 2018/0057840 A1; supra) and Hamming (The Journal of Pathology (2004) 203: 631-637; supra).
The teachings of the co-pending reference application are discussed in the non-statutory double patenting rejection above.
However, the co-pending reference application does not teach a recombinant AAV particle comprising a nucleic acid sequence encoding the claimed anti-ACE2 monoclonal antibody or methods of administering such a recombinant AAV for treatment or prophylaxis of a human subject infected with SARS-CoV-2.
The teachings of Hauswirth and Hamming are discussed in the 35 U.S.C. § 103 rejection above.
Based on the further teachings of Hauswirth and Hamming, 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 methods recited in the co-pending claims by administering to the subject in need thereof a recombinant AAV vector comprising a nucleic acid encoding the anti-ACE2 antibody of the invention in order to treat or reduce the likelihood of infection with SARS-CoV-2. The skilled artisan would have been motivated to do so because Hauswirth teaches that rAAVs have utility in treating disease and have several advantages as therapeutic delivery systems (e.g., reduced immunogenicity, resistance to proteasomal degradation). There would have been a reasonable expectation of success because the rAAV constructs described by Hauswirth target VECs, and ACE2 is known to be expressed in VECs as shown by Hamming. Therefore, the rAAV construct encoding an anti-ACE2 antibody (such as that recited in the co-pending claims) would effectively be targeted to the ACE2-expressing cells that are vulnerable to SARS-CoV-2 infection.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(4)
Claims 1-8, 10-12, and 15-34 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of co-pending Application No. 17/996,019 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the co-pending claims clearly anticipate the instantly claimed invention.
Co-pending claims 1-3 recite a monoclonal antibody (mAb) with identical functional properties to that of claims 1-3.
Co-pending claims 4 and 6 recite identical epitopes to which the co-pending mAb does not bind as instant claims 4 and 6. Co-pending claim 5 recites that the co-pending mAb does not bind an epitope comprising residues 290-397 or 417-430 of hACE2, as is also recited in claim 5. Co-pending claim 7 recites identical residues as claims 7-8 to which the co-pending mAb specifically binds.
Co-pending claims 9-14 recite identical limitations to claims 10-12 and 15-17, respectively.
Co-pending claims 15-16 recite an identical prophylactic method to that of claims 18-19. Co-pending claims 17-19 recite an identical treatment method to that of claims 20-22.
Co-pending claims 20-23 recite an identical recombinant AAV vector and a composition comprising the same, as recited in claims 23-26. Co-pending claims 24-28 recite identical prophylactic and treatment methods for administering said recombinant AAV as recited in claims 27-31.
Co-pending claims 29-31 recites identical kits to those recited in instant claims 32-34.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(5)
Claim 9 is provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of co-pending Application No. 17/996,019 (reference application) as applied to claims 1-8, 10-12, and 15-34 above, further in view of Du (Nature Communications (2021) 12: 5000; supra).
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
However, the co-pending reference application does not teach that the monoclonal antibody comprises three heavy chain CDRs comprising the amino acid sequences of SEQ ID NO: 2-4, respectively, and three light chain CDRs comprising the amino acid sequences of SEQ ID NO: 5-7, respectively.
The teachings of Du, with respect to such an antibody (11B11) that also possesses the functional attributes recited in claim 1, is summarized in the rejections under 35 U.S.C. § 112(a) and § 102 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 monoclonal antibody of the co-pending claims with the 11B11 antibody disclosed by Du, e.g., in a method of treatment or prophylaxis of a SARS-CoV-2-mediated disease. The skilled artisan would have been motivated to do so because such an antibody would have utility in treating a SARS-CoV-2 infection (i.e., preventing the virus from binding to host cells) while allowing the host ACE2 to retain normal or mostly normal function. There would have been a reasonable expectation of success because one of ordinary skill in the art would recognize that the antibodies recited in the co-pending reference application and by Du are functional equivalents useful for the same purpose.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
(6)
Claims 13-14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-31 of co-pending Application No. 17/996,019 (reference application) as applied to claims 1-8, 10-12, and 15-34 above, further in view of Lazar (US 2015/0071948 A1; supra), Hale (WO 2021/234402 A2; supra), and Shitara (U.S. Patent No 8,883,981; supra)..
The teachings of the co-pending reference application are recited in the non-statutory double patenting rejection above.
However, the co-pending claims do not recite that the monoclonal antibody comprises an isotypically IgG1 heavy chain comprising an amino acid sequence corresponding to residues 25-471 of SEQ ID NO: 77 (as set forth in Figure 7 and claim 13) or residues 25-471 of SEQ ID NO: 78 (as set forth in Figure 8 and claim 14).
The teachings of Lazar, Hale, and Shitara are discussed in the 35 U.S.C. § 103 rejection above.
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 an anti-ACE2 monoclonal antibody having a modified heavy chain comprising an amino acid sequence corresponding to residues 25-471 of instant SEQ ID NO: 77 or 78, and a light chain comprising an amino acid sequence corresponding to residues 21-230 of instant SEQ ID NO: 76, through a process of routine optimization. The skilled artisan would have been motivated to use an isotypically IgG1 heavy chain because Lazar teaches that the different IgG antibody subtypes have differences in stability, solubility, FcγR-mediated effector functions, complement-mediated effector functions, in vivo pharmacokinetics, and oligomerization states. These differences affect their therapeutic properties and can be optimized for desired qualities. There would have been a reasonable expectation of success because it is within the technical skill of those in the art to generate IgG antibodies of differing isotypes and/or introduce mutations thereto, and furthermore, there are a finite number of possible IgG Fc structures.
The skilled artisan would further have been motivated to substitute the residues “STR” at positions 234-236 because Hale teaches that this modification reduces FcγR binding while retaining FcRn binding (which improves serum half-life), as well as the substitutions of M252Y/S254T/T256E, as Hale teaches that these modifications also improve serum half-life. There would have been a reasonable expectation of success because the skilled artisan would have recognized that these modifications have suitability for the intended purpose of increasing serum half-life, which is beneficial for antibody-based therapeutics, and it is prima facie obvious to apply a known technique to a known product ready for improvement to yield a predictable result.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claims are allowed.
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/ELIZABETH A SHUPE/Examiner, Art Unit 1643
/JULIE WU/Supervisory Patent Examiner, Art Unit 1643