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 .
Claim Status
Claims 1-12 and 14-21 are pending and under examination in the instant office action.
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.
Claim 1-12 and 14-21 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Regarding claims 1 and 2, the claims recite a single variable domain comprising complementarity determining regions comprising “CDR1 comprising the amino acid sequence set forth in SEQ ID NO: […] 5, […] 17, […]” (e.g., claim 1), but SEQ ID NOs: 5 and 17 are undefined in the sequence listing due to ST.26 format skipping all sequences of less than four amino acids. Therefore claims 1 and 2 fail to delineate the metes and bounds of the subject matter that Applicant regards as the invention with the requisite clarity and particularity to permit the skilled artisan to know or determine the infringing subject matter. Claim amendment to recite the three amino acids (‘SVA’, See Specification p. 16 Table S1) and two amino acids (‘MG’ See Specification p. 16 Table S1), respectively directly in the claim rather than SEQ ID NO: 5 and 17 would circumvent the rejection due to the ST.26 XML format not allowing sequence listings of less than four amino acids.
Dependent claims are rejected for failing to resolve the indefiniteness as described.
The term “preferably” in claim 5 (line 3) is an exemplary term which renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). It is suggested the applicant revise the claims to remove the term “preferably” and the limitations following it.
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, 4-12 and 14-21 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.
Regarding claim 1, the alternate claiming of the CDRs 1-3 allow for mixing-and-matching of CDRs within the single variable domain that is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the recited function of binding c-Met.
Scope of the claimed genus
Regarding claim 1, the claim recites an isolated antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof bind to c-Met and comprises at least one single variable domain, wherein the single variable domain comprises the CDRs: (a) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, 8, 5, 14, 17, or 20; (b) CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, 9, 6, 15, 18, or 21; and (c) CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, 10, 7, 16, 19, or 22.
Claims 4-12 and 14-21 are ultimately dependent on claim 1 without further limiting the scope of the mix-and-match of the CDRs.
State of the Relevant 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) which provide the majority of the contact residues for the binding of the antibody to its target epitope. E.g., Almagro et. al., Front. Immunol. 2018; 8:1751 (see Section “The IgG Molecule” in paragraph 1 and Figure 1). While affinity maturation techniques can result in differences in the CDRs of the antibody compared to its parental antibody (page 3 “The IgG Molecule, second and third paragraphs), those techniques involve trial-and-error testing and the changes that maintain or improve affinity are not predictable a priori. E.g., id., (page 6 ending paragraph onto page 7). Chiu ML et al. (Antibodies 2019 8, 55, 1-80) taught the antigen binding of antibodies often results in conformational changes in the contact surface areas of both the antibody and the antigen (page 5, first paragraph). Thus, the prediction of CDR binding to the epitope is difficult to predict. Chiu further taught antibody modeling has been shown to be accurate for the framework region sequences, but CDR modeling requires further development and improvements (page 6, second paragraph). Prediction of the structure of HCDR3 could not be accurately produced when given the Fv structures without their CDR-H3s (page 6, second paragraph). Chiu taught the quality of antibody structure prediction, particularly regarding CDR-H3, remains inadequate, and the results of antibody–antigen docking are also disappointing (page 11, paragraph 2).
VHH Antibodies
At the time of filing, VHH antibody antigen binding domain functionality was known to depend on the entire structure, particularly a full complement of three CDRs. It is understood by one of ordinary skill in the art that that uncharacterized CDR binding is unpredictable and that each construct requires function testing.
Bever et al. (Anal Bioanal Chem (2016) 408:5985–6002; hereinafter “Bever”) teaches VHH antibodies, and the production and screening thereof [e.g., title, abstract]. Bever teaches Nanobodies® are VHH domain antibodies that are heavy chain only (e.g. HcAb) that are naturally produced by camelids and sharks [e.g., pg. 5985, “Introduction”]. Bever teaches the overview of process of making VHH antibodies wherein (1) an alpaca is the camelid species, (2) mRNA is collected from the alpaca and a cDNA library is constructed therefrom, (3) VHH genes are isolated, (4) a phage-display VHH library is generated, (5) solid phase panning conducted to select the desired VHH, and (6) desired VHH is obtained [e.g., fig. 2].
Hacisuleyman and Erman (Journal of Biological Physics (2020) 46:189–208; hereinafter “Hacisuleyman”) teaches VHH optimization [e.g., title, abstract]. Hacisuleyman teaches VHH antibodies comprise 3 CDRs which determine target specificity, with CDR3 being the “dominating contributor in antigen recognition” [e.g., pg. 191; fig. 2]. Hacisuleyman further teaches residue numbers for the VHH CDRs may vary, and that in nature CDRs are mutated naturally to increase the binding affinity and specificity towards a target antigen [e.g., pg. 191]. Hacisuleyman teaches that computational screening methods for optimization are a first step that is then followed by experimental strategies [e.g., pg. 191]. Hacisuleyman does not support mix-and-match generation of VHH CDRs to bind a selected target, but rather requires the researcher start with a VHH antibody known to bind the target antigen [e.g., 191].
Other VHH anti-c-Met antibodies have been disclosed in the art. For example, CN110964107A to Xu et. al. published 7 April, 2020 teaches heavy chain only anti-c-Met antibodies (Abstract; citations to machine translation).
Methods of Treatment
At the time of filing, Puccini, Alberto, et al. "Safety and Tolerability of c-MET Inhibitors in Cancer: A. Puccini et al." Drug safety 42.2 (2019): 211-233 (hereinafter “Puccini”) taught anti-c-Met antibodies were being developed in the art as a therapeutic for c-Met positive cancers (e.g., “New Agents Under Development” section, ¶1-6 ]. Puccini taught that multiple anti-c-Met antibody clinical trials were underway but had mixed results or the results have not been reported. For example, Puccini et. al. teaches that “evaluating the addition of onartuzumab to first-line chemotherapy with mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) in HER2-negative, c-MET-positive metastatic gastric or GEJ cancers, and a randomized phase II study, investigating the activity of onartuzumab plus first-line FOLFOX-bevacizumab in CRC, failed to demonstrate significant results”.
Summary of Species disclosed in the original specification
The instant specification discloses five species of single-domain anti-c-Met antibodies: 1B-3B11, 1B-1B6, 1B-1C7, 1B-1A8, 1B-1B2, and 3B-1C7 (Table S1 and S2 p. 16-17). The specification teaches that, as VHH-Fc chimeric antibodies, the antibodies bound to c-Met (Example 3.2, Table 1) and cell lines expressing c-Met (Example 4). The specification further teaches that all five antibodies can block the binding of HGFβ to the c-Met receptor (Example 5); can block c-Met phosphorylation downstream of HGF stimulation (Example 6); and can inhibit the proliferation of KP4 cells, which are a human c-Met positive pancreatic ductal adenocarcinoma cell line. There are no examples of CDR mix-and-match in the instant specification.
Summary
A genus of species is not present in the instant specification or prior art that would demonstrate a structure/activity relationship would be known for antibody CDR residues for the recited function of binding the protein c-Met. There is a lack of an appropriate number of species with CDR mix-and-matching to determine which CDR residues: i) are essential for binding; ii) can be changed and still allow protein target binding; or iii) disrupt protein target binding. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of substitutions and deletions of the polypeptide of claim 1 at the time of filing. Regarding claims 4-12 and 14-21 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 112(a)- Scope of Enablement
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 16-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method for inhibiting tumor cell growth or killing a tumor cell, or a method of treating comprising administering to the subject having a tumor the antibody or antigen-binding fragment of claim 1 wherein: 1) the cancer expressed c-Met and 2) wherein the tumor is pancreatic cancer
does not reasonably provide enablement for a method of inhibiting tumor cell growth or killing a tumor cell, or a method of treating: 1) any generic cancer regardless of c-Met expression and 2) wherein the tumor is any tumor type
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is "undue." These factors include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
Scope of the claimed genus and nature of the invention
Claim 16 recites a method for inhibiting tumor cell growth or killing a tumor cell comprising administering to the tumor cell an effective amount of the antibody or antigen-binding fragment thereof according to claim 1. Claim 17 recites a method for treating a subject having a tumor, comprising administering to the subject a therapeutically effective amount of the antibody or the antigen-binding fragment thereof according to claim 1.
Regarding claim 1, the claim recites an isolated antibody or antigen-binding fragment thereof, wherein the antibody or antigen-binding fragment thereof bind to c-Met and comprises at least one single variable domain, wherein the single variable domain comprises the CDRs: (a) CDR1 comprising the amino acid sequence set forth in SEQ ID NO: 11, 8, 5, 14, 17, or 20; (b) CDR2 comprising the amino acid sequence set forth in SEQ ID NO: 12, 9, 6, 15, 18, or 21; and (c) CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 13, 10, 7, 16, 19, or 22.
Claims 18 and 19 narrow claims 16 and 17, respectively, to recited wherein the tumor is selected from a large group of tumor types.
State of the Relevant Art; level of one of ordinary skill; and level of predictability of the art
Other VHH anti-c-Met antibodies have been disclosed in the art. For example, CN110964107A to Xu et. al. published 7 April, 2020 teaches heavy chain only anti-c-Met antibodies (Abstract; citations to machine translation).
Methods of Treatment
At the time of filing, Puccini, Alberto, et al. "Safety and Tolerability of c-MET Inhibitors in Cancer: A. Puccini et al." Drug safety 42.2 (2019): 211-233 (hereinafter “Puccini”) taught anti-c-Met antibodies were being developed in the art as a therapeutic for c-Met positive cancers (e.g., “New Agents Under Development” section, ¶1-6 ]. Puccini taught that multiple anti-c-Met antibody clinical trials were underway but had mixed results or the results have not been reported. For example, Puccini et. al. teaches that “evaluating the addition of onartuzumab to first-line chemotherapy with mFOLFOX6 (oxaliplatin, 5-fluorouracil and leucovorin) in HER2-negative, c-MET-positive metastatic gastric or GEJ cancers, and a randomized phase II study, investigating the activity of onartuzumab plus first-line FOLFOX-bevacizumab in CRC, failed to demonstrate significant results”.
Lee, Dongheon, et al. "Development of antibody-based c-Met inhibitors for targeted cancer therapy." ImmunoTargets and therapy (2015): 35-44 (hereinafter “Lee”) teaches that the HGF/c-Met signaling pathway is activated in human cancers via overexpression, amplification, or mutation to promote cancer and that c-Met overexpression has been reported in solid tumors including breast, colon, lung, ovary, kidney, liver (p. 37 right column-p. 38 left column). Lee teaches that antibodies against HGF and c-Met suppress the signaling pathway by blocking HGF/c-Met and that multiple antibodies targeting this pathway are in preclinical and clinical development (p. 39 left column). Lee teaches that “There are important aspects of HGF/c-Met biology that need to be carefully addressed for successful development of these therapeutic antibodies targeting the HGF/c-Met signaling pathway. These include unwanted activation of c-Met by bivalent anti-c-Met antibodies and the recent failure of the Phase III study of onartuzumab in combination with erlotinib in NSCLC” (p. 40 right column-p. 41 left column ¶1). Lee teaches that it is important to consider patient stratification and effective combination therapies and that, “it is critical to more accurately detect c-Met expression levels and alterations” (p. 45 left column). Lee finally states “Results from clinical studies reflect the highly complex nature of HGF/c-Met signaling in human cancers and suggest that successful development of antibody-based therapeutics targeting the HGF/c-Met signaling pathway requires a better understanding of the pathways involved in the diseases, along with more careful analyses of the clinical data” (p. 41 right column ¶4). This suggests that, at the time of filing, methods of treating tumors with anti-c-Met antibodies were not predictable and were dependent on the antibody structure, the c-Met expression in the target cancer or tumor, and the etiological subtype of the cancer. Thus, although the level of skill in the art is high, the level of unpredictability is also high.
Summary of Species disclosed in the original specification; the amount of direction provided by the inventor, existence of working examples; and quality of experimentation needed to make or use the invention based on the content of the disclosure.
The instant specification discloses five species of single-domain anti-c-Met antibodies: 1B-3B11, 1B-1B6, 1B-1C7, 1B-1A8, 1B-1B2, and 3B-1C7 (Table S1 and S2 p. 16-17). The specification teaches that, as VHH-Fc chimeric antibodies, the antibodies bound to c-Met (Example 3.2, Table 1) and cell lines expressing c-Met (Example 4). The specification further teaches that all five antibodies can block the binding of HGFβ to the c-Met receptor (Example 5); can block c-Met phosphorylation downstream of HGF stimulation (Example 6); and can inhibit the proliferation of KP4 cells, which are a human c-Met positive pancreatic ductal adenocarcinoma cell line. There are no examples of administering the instant antibodies to a subject, or of methods of contacting other types of tumor cells or non-c-Met positive tumor cells with the antibody.
Conclusion
Applicant does not have enablement for a method of killing or inhibiting any generic tumor cell growth or treating a subject having any generic tumor wherein the tumor is not required to express c-Met or any can be one from a large group of cancers. It would take undue experimentation for a person of ordinary skill in the art to determine which etiologically distinct cancers that may or may not express c-Met, including hematological tumors, would be inhibited, killed, or treated by the instantly claimed antibodies.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-9, 12 and 15-21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 19362014 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '014 anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ‘014 teach a multispecific antibody comprising a first antigen-binding moiety to c-Met, wherein the first antigen-binding moiety is a single variable domain and comprises e.g. SEQ ID NOs: 7, 8, and 9, respectively (identical to instant SEQ ID NO: 11, 12, and 13, respectively) (claims 1 and 2). The claims also teach a c-Met binding antibody wherein the single variable domain comprises e.g. SEQ ID NO: 7, 8, and 9 and the single variable domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 27 (identical to instant SEQ ID NO: 28).
Regarding claim 3, claim 3 teaches where the first antigen-binding moiety may comprise an amino acid sequence having at least 85% identity to a sequence selected from a group including SEQ ID NO: 27; SEQ ID NO: 27 is identical to instant SEQ ID NO: 28.
Regarding claim 4, although the claims to not explicitly recite that the single domain variable chain is a VHH, this is an inherent property of SEQ ID NO: 27 because a VHH is the variable domain of a heavy-chain only antibody to which the claims of ‘014 are directed.
Regarding claim 5, claim 11 teaches wherein the multispecific further comprises an Fc domain.
Regarding claim 6, the claim teaches particular properties or characteristics of the heavy chain antibodies. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Regarding claim 7, the claimed multispecific comprising an Fc domain as described above is a fusion protein.
Regarding claims 8 and 20, claim 18 teaches the multispecific and a pharmaceutically acceptable excipient.
Regarding claim 9 and 21, claim 15 teaches a nucleic acid encoding the multispecific antibody.
Regarding claim 12, claim 16 teaches a method for preparing the multispecific antibody comprising the nucleic acid to express the antibody and isolating and purifying the multispecific antibody. Regarding claims 15-19, claim 19 teaches a method for treating a disease expressing c-Met comprising administering to a subject a therapeutically effective amount of the multispecific antibody wherein the disease is a tumor and the tumor is selected from a group of cancers overlapping with those recited in instant claims 18-19.
Claims 10-11 and 14 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 19362014 (reference application) as applied to claims 1 and 9 above, and further in view of CN110964107 to Xu et. published 7 April 2020 (citations to machine translation).
This is a provisional nonstatutory double patenting rejection.
The teachings of the ‘014 patent in regard to claims 1 and 9 are in the NSDP rejection above.
The ‘014 application does not explicitly teach a vector comprising the nucleic acid encoding the antibody and a host cell encoding the antibody.
This deficiency is resolved by Xu et. al.
Xu et. al. teaches an anti-MET (equivalent to c-MET) VHH antibody. Xu et. al. teaches nucleic acids encoding the antibody, vectors comprising the nucleic acids, and host cells comprising them.
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to encode the nucleic acids encoding the antibody in vectors comprising the nucleic acids, and to make host cells comprising the nucleic acids to encode the antibodies as taught by Xu et. al. This would have a predictable effect because it was routine in the art as taught by Xu et. al. to express antibodies with host cells and vectors (e.g. p. 17, middle; p. 25, top).
Regarding claim 14, the ‘014 claims to not teach a method of detecting c-Met in a sample comprising contacting the antibody with the sample and detecting the binding complex.
This deficiency is resolved by Xu et. al.
Xu et. al. teaches a method of detecting MET comprising contacting a biological sample with the anti-MET VHH antibody and detecting the formation of the complex (e.g. p. 81 bottom-p. 82 top, claim 28; p. 23 bottom).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the antibody of the ‘014 claims in a method of detection of c-Met in order to benefit from an alternate anti-c-Met VHH for detecting c-Met as taught by Xu et. al. This would have a predictable effect because the claims of ‘014 teach the antibody and a person of ordinary skill in the art would expect to be able to use in a method of detection.
Claims 1-8 and 15-20 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 21-41 of copending Application No. 19532354 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of '354 anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
The claims of ‘354 teach an antibody drug conjugate comprising a first antigen-binding moiety to c-Met, wherein the first antigen-binding moiety is a single variable domain and comprises e.g. SEQ ID NOs: 7, 8, and 9, respectively (identical to instant SEQ ID NO: 11, 12, and 13, respectively) (claims 1 and 2). Regarding claim 3, the claims also teach a c-Met binding antibody wherein the single variable domain comprises e.g. SEQ ID NO: 7, 8, and 9 and the single variable domain comprises an amino acid sequence at least 85% identical to SEQ ID NO: 36 (92.8% identical to instant SEQ ID NO: 28) as shown below:
Query Match 92.8%; Score 630; DB 1; Length 128;
Best Local Similarity 92.2%;
Matches 118; Conservative 5; Mismatches 5; Indels 0; Gaps 0;
Qy 1 QVQLVESGGGSVQPGGSLRLSCAASGYSYSANCVGWFRQAPGKGREGVSAINTGGETATY 60
|||||||||| |||||||||||||||||||||||||| ||||| ||||:|||||||||||
Db 1 QVQLVESGGGLVQPGGSLRLSCAASGYSYSANCVGWFYQAPGKEREGVAAINTGGETATY 60
Qy 61 ADFVKGRFTISRDNAKNTVYLQMNSLRAEDTAVYYCAAVGTRKYWDECSLSQHAYKNWGQ 120
|||||||||||:| ||||||||||||::||| :|||||||||||||||||||||||||||
Db 61 ADFVKGRFTISQDYAKNTVYLQMNSLKSEDTGMYYCAAVGTRKYWDECSLSQHAYKNWGQ 120
Qy 121 GTLVTVSS 128
||||||||
Db 121 GTLVTVSS 128
Regarding claim 4, although the claims to not explicitly recite that the single domain variable chain is a VHH, this is an inherent property of SEQ ID NO: 36 because a VHH is the variable domain of a heavy-chain only antibody to which the claims of ‘354 are directed.
Regarding claim 5, claim 28 teaches wherein the multispecific further comprises an Fc domain.
Regarding claim 6, the claim teaches particular properties or characteristics of the heavy chain antibodies. Applicant is reminded that products of identical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. In re Spada 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). See MPEP 2112.01.
Regarding claim 7, the claimed ADC comprising an Fc domain as described above is a fusion protein.
Regarding claims 8 and 20, claim 39 teaches the multispecific and a pharmaceutically acceptable excipient. Regarding claims 15-19, claims 40-41 teaches a method for treating a disease expressing c-Met comprising administering to a subject a therapeutically effective amount of the multispecific antibody wherein the disease is a tumor and the tumor is selected from a group of cancers overlapping with those recited in instant claims 18-19.
Claims 9-12, 14, and 21 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 1-20 of copending Application No. 19362014 (reference application) as applied to claims 1 and 9 above, and further in view of CN110964107 to Xu et. published 7 April 2020 (citations to machine translation).
This is a provisional nonstatutory double patenting rejection.
The teachings of the ‘014 patent in regard to claims 1 and 9 are in the NSDP rejection above.
Regarding claims 9-12, and 21, The ‘014 application does not explicitly teach a vector comprising the nucleic acid encoding the antibody and a host cell encoding the antibody.
This deficiency is resolved by Xu et. al.
Xu et. al. teaches an anti-MET (equivalent to c-MET) VHH antibody. Xu et. al. teaches nucleic acids encoding the antibody, vectors comprising the nucleic acids, and host cells comprising them, including methods of making the antibody comprising culturing a host cell comprising the expression vector and isolating the antibody (e.g. p. 17, middle; p. 25, top).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to encode the nucleic acids encoding the antibody in vectors comprising the nucleic acids, and to make host cells comprising the nucleic acids to encode the antibodies as taught by Xu et. al. and perform methods of making the antibody. This would have a predictable effect because it was routine in the art as taught by Xu et. al. to express antibodies with host cells and vectors.
Regarding claim 14, the ‘014 claims to not teach a method of detecting c-Met in a sample comprising contacting the antibody with the sample and detecting the binding complex.
This deficiency is resolved by Xu et. al.
Xu et. al. teaches a method of detecting MET comprising contacting a biological sample with the anti-MET VHH antibody and detecting the formation of the complex (e.g. p. 81 bottom-p. 82 top, claim 28; p. 23 bottom).
It would have been obvious, at the time of filing, for a person of ordinary skill in the art to use the antibody of the ‘014 claims in a method of detection of c-Met in order to benefit from an alternate anti-c-Met VHH for detecting c-Met as taught by Xu et. al. This would have a predictable effect because the claims of ‘014 teach the antibody and a person of ordinary skill in the art would expect to be able to use in a method of detection.
Allowable Subject Matter
Claims 2would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kathleen CunningChen whose telephone number is (703)756-1359. The examiner can normally be reached Monday - Friday 11-8:30 ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gregory Emch can be reached at (571) 272-8149. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KATHLEEN CUNNINGCHEN/ Examiner, Art Unit 1646
/GREGORY S EMCH/ Supervisory Patent Examiner, Art Unit 1678
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