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
Instant claims 1-9, 11-12, 16-23, and 25 are pending and under examination in the instant office action.
Priority
The claim to domestic benefit for applications PCT/CA2022/051074 filed 7/9/2022 and provisional application 63/203126 field 7/9/2021 is acknowledged.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Formal Matters
The Examiner notes that the claims are directed towards two antibodies, one of which comprises a VH and VL of SEQ ID NOs: 21 and 22 (antibody #3). Claims 4-5 and 6-7 are directed towards the antibody framework regions of antibody #3; however, the examiner notes that the light chain FR4 SEQ ID NO: 48 FGQGTKLEIK is different from the FR4 region present in SEQ ID NO: 22 residues 98-107 by one residue:
Title: US-18-576-567-22
Perfect score: 548
Sequence: 1 EIVLTQSPGTLSLSPGERAT..........YCQQYGSSYTFGQQTKLEIK 107
Scoring table: BLOSUM62
Gapop 10.0 , Gapext 0.5
Searched: 1 seqs, 10 residues
Total number of hits satisfying chosen parameters: 1
Minimum DB seq length: 0
Maximum DB seq length: inf
Post-processing: Minimum Match 0%
Maximum Match 100%
Listing first 50 summaries
Database : US-18-576-567-48.fasta:*
SUMMARIES
%
Result Query
No. Score Match Length DB ID Description
----------------------------------------------------------------------------
1 43 7.8 10 1 US-18-576-567-48 NOVEL NEUTRALIZING
ALIGNMENTS
RESULT 1
US-18-576-567-48
Query Match 7.8%; Score 43; DB 1; Length 10;
Best Local Similarity 90.0%;
Matches 9; Conservative 0; Mismatches 1; Indels 0; Gaps 0;
Qy 98 FGQQTKLEIK 107
||| ||||||
Db 1 FGQGTKLEIK 10
Although there is no claim rejection, the Examiner requests clarification whether the change to SEQ ID NO: 48 was inadvertent and was meant to be identical to SEQ ID NO: 22 residues 98-107 as described in the specification.
Specification
The disclosure is objected to because of the following informalities: As described in the "Formal Matters" section above, the specification identifies SEQ ID NO: 48 as FR4 of antibody #3; however there is one residue different between SEQ ID NO: 48 and residues 98-107 of FR4 of SEQ ID NO: 22, which is the complete VL of antibody #3 (See p. 3 lines 35-36, p. 4 line 7, Table 2, p. 21 lines 26 and 32-33, and the list of sequence table on p. 45). It is unclear how the VL FR4 and the FR4 alone from the same antibody could have distinct sequences.
Appropriate correction is required.
Claim Objections
Claim 1 is objected to because of the following informalities: Claim 1 recites "An antibody or an antigen binding fragment thereof comprises one of the following combinations of complementarity determining regions (CDRs)" (emphasis is the Examiner’s). The Examiner suggests amending “comprises” to “comprising” which is the gerund form of the verb or adding a transitional word such as “which comprises”. Appropriate correction is required.
Claims 2 and 3 recite the antibody which comprises “the following combinations of complementarity determining regions (CDRs)” after which a single combination is recited. The Examiner suggests amending “combinations” to “combination”.
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 7, 21 and 25 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.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 7 recites the broad recitation at least 50%, and the claim also recites 60%, 70%, 75%, 80%, 85%, 90%, or 95% identity withe the sequence which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Regarding claims 21, the parenthetical “(COVID-19)” renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention (i.e. whether COVID-19 the only SARS-CoV-2 infection-related disease treated). See MPEP § 2173.05(d). It is suggested the applicant amend the claim to remove the parenthetical.
Regarding claim 25, the claim recites “at least one additional anti-SARS-CoV-2 antibody or antigen-binding fragment thereof”; however, claim 21 from which claim 25 depends recites only the antibody or antigen-binding fragment of claim 1 and claim 1 does not require the antibody or antigen-binding fragment thereof is an anti-SARS-CoV-2 antibody. Therefore, the antecedent basis of the “at least one additional anti-SARS-CoV-2” antibody is unclear. The Examiner suggests the rejection may be obviated by reciting “An anti-SARS-CoV-2 antibody or antigen binding fragment thereof” in claim 1.
Claim Rejections - 35 USC § 112(a)- Written Description
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, 4-9, 16-23, and 25 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 antibody or antigen binding fragment thereof only requires 70% identity to each CDR allow for changes to the CDR within the VH and VL of the antibody which is the binding determinant region, but the art and genus of known species does not allow for predictable binding of the function described in the specification of binding SARS-CoV-2 glycoprotein receptor binding domain (RBD).
Regarding claim 17, the claim recites a nucleic acid comprising a sequence encoding the light chain or the heavy chain of the antibody or antigen binding fragment of claim 1, and therefore the claim is directed towards an even broader genus of nucleic acids including those encoding antibodies with a complete heavy or light chain swap.
Regarding claims 21 and 25, Claim 21 is directed at a method of treating or preventing a SARS-CoV2 infection or related disease in a subject comprising administering the antibody or antigen binding fragment thereof of claim 1, a conjugate or chimeric antigen receptor comprising said antibody, one or more nucleic acids comprising a sequence encoding said antibody, or a pharmaceutical composition comprising said antibody or said one or more nucleic acids. Claim 25 is directed at the method of claim 21 wherein the antibody, antigen-binding fragment thereof, conjugate, CAR, one or more nucleic acids, or pharmaceutical composition is administered with at least one additional anti-SARS-CoV-2 antibody or antigen-binding fragment thereof. The instant specification defines “preventing” as “administration of the agent prior to infection that leads to protection from being infected or from developing the viral disease (e.g. COVID-19), to a delay in the development of the disease, or to a reduction of one or more symptoms or pathological feature associated with the viral disease” (p. 37 lines 28-32).
Scope of the claimed genus
Claim 1 recites a genus of polypeptides comprising an antibody binding fragment which comprises a combination of CDRs with either a) light chains CDRs 1-3 SEQ ID NOs: 14, 17, and 19, or amino acid sequences having at least 70% identity to SEQ ID NOs: 14, 17, and 19 and heavy chain CDRs 1-3 SEQ ID NOs: 1, 6 and 11 or amino acid sequences having at least 70% identity to SEQ ID NOs: 1, 6, and 11, or b) light chain CDRs 36, 39, and 41 or amino acid sequences having at least 70% identity to SEQ ID NOs: 36, 39, and 41, and heavy chain CDRs 1-3 SEQ ID NOs: 23, 28, and 33 or amino acid sequences having at least 70% identity to SEQ ID NOs: 23, 28, and 33. There are no functional limitations recited in the claims, such as the binding target of the antibodies.
Claim 17 is directed at a nucleic acid encoding either the heavy chain or the light chain of the antibody, and is therefore broader than the instantly claimed antibody of claim 1 because it allows complete swapping of either the heavy or light chain.
Claim 21 is directed at a method of treating or preventing a SARS-CoV2 infection or related disease in a subject comprising administering the antibody or antigen binding fragment thereof of claim 1, a conjugate or chimeric antigen receptor comprising said antibody, one or more nucleic acids comprising a sequence encoding said antibody, or a pharmaceutical composition comprising said antibody or said one or more nucleic acids. Claim 25 is directed at the method of claim 21 wherein the antibody, antigen-binding fragment thereof, conjugate, CAR, one or more nucleic acids, or pharmaceutical composition is administered with at least one additional anti-SARS-CoV-2 antibody or antigen-binding fragment thereof. The instant specification defines “preventing” as “administration of the agent prior to infection that leads to protection from being infected or from developing the viral disease (e.g. COVID-19), to a delay in the development of the disease, or to a reduction of one or more symptoms or pathological feature associated with the viral disease” (p. 37 lines 28-32). However, the instant specification does not define protection from being infected or what is considered an infection. Therefore, the broadest reasonable interpretation (BRI) of “protection from being infected” is based on the definition in the art; for example, “Webster’s New World Medical Dictionary” defines a viral infection as “An infection caused by the presence of a virus in the body” (Viral infection. (2008). In Web MD, Webster’s New World Medical Dictionary (3rd ed.). Houghton Mifflin. https://access.infobase.com/article/10767163-viral-infection?aid=279753). The BRI of protection from being infected includes, therefore, protection of a subject from having the virus present in the body.
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).
Further, a recitation of “percent identity” does not limit the differences in amino acid sequence to residues outside the CDRs. And while it is possible to screen for variants that retain antigen binding, it is respectfully submitted that the number of possible substitutions permitted by “70% percent identity” language does not allow the skilled artisan to envisage those variants not yet made which would retain the required function.
Additionally, 70% identity to the CDRs of SEQ ID NOs: 1, 6, 11, 14, 17, and 19 allow for changes to 2, 1, 3, 3, 2, and 2 amino acid residues respectively and 70% identity to the CDRs of SEQ ID NOs: 23, 28, 33, 36, 39, and 41 allow for changes to 2, 1, 3, 4, 2, and 3 amino acid residues respectively.
In regards to anti-RBD antibodies, other anti-RBD antigen binding sites are known in the art. For example, U.S. 20210292393 to Westendorf et. al. teaches an anti-SARS-CoV-2 antibody binding to the RBD having a heavy and light chain variable regions comprising SEQ ID NO: 729 and 730, which lack 70% identity to most of the instant CDRs compared to the instant antibodies as shown (CDRs are bolded):
RESULT 1
AASEQ2_06092026_194932
Query Match 89.0%; Score 543; DB 1; Length 116;
Best Local Similarity 89.0%;
Matches 105; Conservative 6; Mismatches 5; Indels 2; Gaps 1;
Qy 1 EVQLVESGGGLVQPGGSLRLSCAASGITVSSNYMTWVRQAPGKGLEWVSVIYSGGSTFYA 60
|||||||||||:|||||||||||||| |||||||:||||||||||||||||||||||:||
Db 1 EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYSGGSTYYA 60
Qy 61 DSVRGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLEMAGAFDIWGQGTMVTVSS 118
|||:|||||||||||||||||||||||||||||||||||: | |||||:|||||
Db 61 DSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLQGGGG--PWGQGTLVTVSS 116
RESULT 1
AASEQ2_06092026_195819
Query Match 64.6%; Score 354; DB 1; Length 107;
Best Local Similarity 65.4%;
Matches 70; Conservative 13; Mismatches 22; Indels 2; Gaps 2;
Qy 2 IVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQKPGQAPRLLIYGASSRATGIPD 61
| :|||| :|| | |:| |::||||| : : | |||||||:||:|||| ||| :|:|
Db 2 IQMTQSPSSLSASVGDRVTITCRASQGIRND-LGWYQQKPGKAPKLLIYAASSLQSGVPS 60
Qy 62 RFSGSGSGTDFTLTISRLEPEDSAVYYC-QQYGSSYTFGQQTKLEIK 107
|||||||||||||||| |:||| | ||| | | |||| ||:|||
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCLQDYNYPRTFGQGTKVEIK 107
RESULT 1
AASEQ2_06092026_194932
Query Match 54.7%; Score 348.5; DB 1; Length 116;
Best Local Similarity 58.0%;
Matches 69; Conservative 21; Mismatches 26; Indels 3; Gaps 2;
Qy 1 QVQLVQSGAEVKKPGASVKVSCKASGYTFSSYGISWVRQAPGQGLEWMGWISPYNGNTKY 60
:||||:|| : :|| |:::|| |||:| || :||||||||:||||: | |:| |
Db 1 EVQLVESGGGLIQPGGSLRLSCAASGFTVSSNYMSWVRQAPGKGLEWVSVIYS-GGSTYY 59
Qy 61 PQKFQGRVTMTTDTSTNTAYMELRSLRSDDTAVYYCARDLELGGGFDYWGQGTLVTVSS 119
:|| |:: | | || |::: |||::|||||||||||: ||| |||||||||||
Db 60 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCARDLQGGGG--PWGQGTLVTVSS 116
RESULT 1
AASEQ2_06092026_195819
Query Match 38.3%; Score 222.5; DB 1; Length 107;
Best Local Similarity 48.1%;
Matches 52; Conservative 13; Mismatches 36; Indels 7; Gaps 4;
Qy 4 LTQ-PASVSGSPGQSITISCTGTSSDVGSYNLVSWYQQHPDKAPKFMIYEGTKRPSGVSN 62
:|| |:|:| | | :||:| : | | : |||| | |||| :|| : ||| :
Db 4 MTQSPSSLSASVGDRVTITCRASQ---GIRNDLGWYQQKPGKAPKLLIYAASSLQSGVPS 60
Qy 63 RFSGSKSGNTASLTISGLQAEDEADYYCC-SYAGNSTWVFGGGTKLTV 109
||||| || :|||| || || | ||| | | || |||: :
Db 61 RFSGSGSGTDFTLTISSLQPEDFATYYCLQDY--NYPRTFGQGTKVEI 106
Therefore, a person of ordinary skill in the art would not know a priori from the art how to predict what changes to the instantly described CDRs would result in the function as described in the specification of binding and neutralizing the SARS-CoV-2 RBD.
Although some methods of preventing transmission of SARS-CoV-2, and methods of preventing the development of COVID-19 symptoms by reducing viral load are known in the art, there are no known methods that lead to protection from being infected comprising administering neutralizing antibodies to support the instant broadest reasonable interpretation of prevention from being infected. For example, Krittanawong C, et. al. COVID-19 and preventive strategy. Am J Cardiovasc Dis. 2022 Aug 15;12(4):153-169. PMID: 36147788; PMCID: PMC9490164 teaches that methods of preventing include reduction of transmission through handwashing, reduction of aerosols, minimizing hand-to-face contact, masking, and usage of hand sanitizer. Krittanawong et. al. also teaches that vaccination is crucial to preventing COVID-19, especially severe disease; however, this does not necessarily follow that it leads to a reduction in infections and may rather be due to prevention of the most severe disease symptoms from the infection. Krittanawong et. al. further teach that neutralizing antibodies in convalescent plasma is a COVID-19 specific therapy, suggesting that neutralizing antibodies are not known to prevent, but rather to treat disease.
Li, Dapeng, et al. "SARS-CoV-2 neutralizing antibodies for COVID-19 prevention and treatment." Annual review of medicine 73 (2022): 1-16 teaches that challenges for COVID-19 neutralizing antibody development include viral escape mutations (p. 9-10 “Viral Escape Mutations” section), suggesting that no one antibody can interact with, much less prevent, all SARS-CoV-2 variants.
Cohen MS, et. al.; BLAZE-2 Investigators. Effect of Bamlanivimab vs Placebo on Incidence of COVID-19 Among Residents and Staff of Skilled Nursing and Assisted Living Facilities: A Randomized Clinical Trial. JAMA. 2021 Jul 6;326(1):46-55. doi: 10.1001/jama.2021.8828. PMID: 34081073; PMCID: PMC8176388 teaches a method of preventing infection to the point of seropositivity and of preventing COVID-19 comprising administering a neutralizing antibody against SARS-CoV-2 which met the primary endpoint of reduction of moderate or worse severity of COVID-19: “In the resident prevention population, incidence of moderate or worse COVID-19 was also lower among bamlanivimab recipients compared with placebo recipients (8.8% vs 21.7%; odds ratio, 0.20; 95% CI, 0.08-0.49)” (). In this study, infection was defined as testing positive for SARS-CoV-2 by RT-PCR and Cohen et. al. teaches “In the resident prevention population, 15.1% (24 of 159) of resident participants who received bamlanivimab and 31.9% (44 of 138) of residents who received placebo tested positive for SARS-CoV-2 by RT-PCR (odds ratio, 0.24; 95% CI, 0.12-0.51]), with an absolute risk difference of −16.8 (95% CI, −26.4 to −7.2) percentage points (Figure 3A). Among the staff in the prevention population, 19.3% of staff participants in the bamlanivimab group and 19.8% in the placebo group tested positive for SARS-CoV-2 by RT-PCR by week 4 (odds ratio, 0.96; 95% CI, 0.62-1.49), with an absolute risk difference of −0.5 (95% CI, −6.5 to 5.5) percentage points (P = .005 for interaction) (Figure 3B).” Cohen et. al. teaches “Bamlanivimab was also associated with lower rates of infection in residents and high-risk individuals. Participants in the prevention population who received bamlanivimab and acquired SARS-CoV-2 had lower baseline viral loads and shorter time to viral clearance compared with participants who received placebo”; and “In contrast to the resident and high-risk prevention populations, there was no significant difference in incidence of COVID-19 or SARS-CoV-2 infection in low-risk staff participants who received bamlanivimab compared with placebo. Interpretation of this observation yields various hypotheses given that staff (vs residents) could have differential exposures to infected persons (in the facility and in the community); however, these findings are consistent with the hypothesis that administration of neutralizing monoclonal antibodies has maximal effect in older people and in those at high risk of severe disease whose immune response to SARS-CoV-2 infection may be suboptimal”.
Therefore, it was not described in the art at the time of filing a method of prevention of any subject at risk of SARS-CoV-2 infection, and prevention of infection under the instant BRI of the presence of the virus in the body.
Summary of Species disclosed in the original specification
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.
The instant specification discloses three species of monoclonal antibodies that neutralize SARS-CoV-2, two of which are encompassed in the instant claims: antibody #3 (EH3) and antibody #8 (EH8), for which the sequences are described Tables 1-4 of the specification and the list of sequences. The specification teaches one complete VH and one complete VL for each antibody (SEQ ID NOs: 21 and 22, and 43 and 44; p. 44-45). There are no examples of alternate CDR residues that retain binding to RBD.
The instant specification teaches a method of protecting cells from cells from particular strains of SARS-CoV-2 infection whereby the viral infectivity is reduced in for pseudoviral particles bearing the Spike glycoprotein for particular variants in 293T cells expressing ACE2. There are no examples in the specification of prevention of infectivity in a subject rather than a cell to suggest that the genus of antibodies as claimed may prevent the virus from entering (and thus infecting) the body.
Identifying characteristics and structure/function correlation
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. To meet this requirement in the instant case, the specification must describe structural features that the skilled artisan as of the effective filing date would have expected to convey the claimed binding activity. The instant specification teaches that the putative epitope of binding for antibodies #3 and #8 comprises Y421A, F456A, Y473A, E484K, F486V, and S494D and Y421A, Y473A, G476S, T478K, G485D, F486V, N487D and S494D (Example 2, Fig. 4). However, as described in the state of the art section above, describing the epitope is insufficient to convey to an ordinary artisan what the structure of the instant antibodies would be required to bind the epitope. Thus, the specification does not describe sufficient correlation between structure and function to describe the instantly claimed genus.
Regarding the method of preventing SARS-CoV-2, there are no methods of administering the antibody to any subject, either prophylactically or in a method of treatment. The specification describes prophetically that neutralizing antibodies can be used for prevention. Based on the binding and in vitro infectivity assay (Fig. 3), a person of skill in the art would understand that the antibody would be expected to prevent the development of COVID-19 by binding to the SARS-CoV-2 viral particles and decrease their entry into cells via interaction with ACE2. However, this structure/function correlated does not allow an artisan of ordinary skill to understand the Applicant to be in possession of prevention commensurate with the instant definition, such that a viral infection is stopped from entering any cell in the body of the subject, and to understand the structure/function relationship when no methods of preventing are shown in the context of any subject or any of the claimed antibodies.
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 function described in the specification of binding the protein SARS-CoV-2 RBD. There is a lack of an appropriate number of species with identical or alternative amino acid residues within the CDR binding determinant region that indicate which amino acid 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 4-9, 16-23, and 25 the claims are ultimately dependent on the rejected claim 1 without narrowing the claimed subject matter and thus are also rejected.
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 preventing SARS-CoV-2 by administering the instantly claimed antibodies. There is a lack of an appropriate number of methods of preventing infection by administering to subjects and a lack of breadth of antibodies and subjects to show that prevention could be achieved as claimed. One of skill in the art would reasonably conclude that the applicant was not in possession of the genus of methods including preventing infection as claimed. Regarding claim 25 the claim is ultimately dependent on the rejected claim 21 without narrowing the claimed subject matter and thus are also rejected.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 1-4, 6-9, 11-12, 16-20, and 23 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product and natural phenomenon without significantly more. The claim(s) recite(s) a naturally occurring fully human antibody. This judicial exception is not integrated into a practical application because the claims are directed towards the natural product without additional limitations that would differentiate the claimed product from the natural product. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are not additional limitations recited, or they are routine and conventional.
Claims 1-4, 6-9, 11-12, and 16-20 are directed to a natural phenomenon and an abstract idea because the claims recite a natural product (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural product” is: “an antibody or an antigen binding fragment thereof comprises one of the following combinations of complementarity determining regions (CDRs): (a) a light chain CDR1 (CDR-L1) comprising an amino acid sequence having at least 70% identity with the sequence RASQSVSSSYLA (SEQ ID NO:14); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence GASSRAT (SEQ ID NO:17); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence QQYGSSYT (SEQ ID NO:19); a heavy chain CDR1 (CDR-H1) comprising an amino acid sequence having at least 70% identity with the sequence GITVSSN (SEQ ID NO:1); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence YSGGS (SEQ ID NO:6); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence DLEMAGAFDI (SEQ ID NO:11); or (b) a CDR-L1 comprising an amino acid sequence having at least 70% identity with the sequence TGTSSDVGSYNLVS (SEQ ID NO:36); a CDR-L2 comprising an amino acid sequence having at least 70% identity with the sequence EGTKRPS (SEQ ID NO:39); a CDR-L3 comprising an amino acid sequence having at least 70% identity with the sequence CSYAGNSTWV (SEQ ID NO:41); a CDR-H1 comprising an amino acid sequence having at least 70% identity with the sequence GYTFSSY (SEQ ID NO:23); a CDR-H2 comprising an amino acid sequence having at least 70% identity with the sequence SPYNGN (SEQ ID NO:28); and a CDR-H3 comprising an amino acid sequence having at least 70% identity with the sequence DLELGGGFDY (SEQ ID NO:33). As described in the specification, these are the CDRs from the VH and VL of antibody #3 and antibody #8, which are fully human antibodies naturally occurring and isolated from a human subject Patient 12 (Fig. 1, Example 1 p. 39 lines 12-35).
The claims do not amount to significantly more because claims 2-4, 6-9 and 11-12 impose additional limitations on the identity of the CDR or framework amino acid sequences of the naturally occurring antibody, but do not change the structure of the instant natural product from the VH and VL sequences of the naturally occurring antibody, and therefore do not recite any limitations that amount to more than the natural product. The exception is claim 5, which as described in the “Formal Matters” and “Claim Objections” section above, appears to comprise a FR4 mutation relative to the naturally occurring antibody.
Regarding instant claim 16, the claim is directed towards a conjugate or a chimeric antigen receptor comprising the antibody or antigen binding fragment thereof of claim 1. The instant specification defines conjugates: “Thus, in another aspect, the present disclosure provides a conjugate comprising the antibody or antigen-binding fragment thereof described herein and one or more additional molecules or agents (hereinafter secondary molecules or agents). The antibody or antigen-binding fragment thereof may be conjugated to any type of synthetic or natural secondary molecules or agents, such as peptides. proteins, saccharides/polysaccharides, lipids, naturally-occurring or synthetic polymers/co-polymers, etc. to modify one or more properties of the antibody or antigen-binding fragment thereof” (p. 26 lines 5-11). Therefore, a person of ordinary skill in the art would understand the “conjugate” to include any secondary molecule conjugated to the instant antibody, which would include naturally occurring post-translational modifications of the antibody such as glycosylation, which is addition of a saccharide or polysaccharide that occurs to modulate the binding of the antibody to Fc receptors (see Jennewein, Madeleine F., and Galit Alter. "The immunoregulatory roles of antibody glycosylation." Trends in immunology 38.5 (2017): 358-372).
Claim 17 recites a nucleic acid comprising a sequence encoding the light chain and/or heavy chain of the antibody or antigen binding fragment of claim and claim 18 recited a host cell comprising the nucleic acid. The instant specification describes the natural encoding nucleic acids and host cells (PBMCs) of the patient 12, and therefore are also products of nature.
Regarding claim 19, the instant specification teaches that an excipient has its normal meaning in the art and is any ingredient that is not an active ingredient (drug) itself (p. 32 lines 17-18). Thus, the broadest reasonable interpretation (BRI) of the instant pharmaceutical composition comprising an excipient includes human plasma or blood comprising the instant antibody, which is not markedly different from the instant natural product because the blood or plasma of Patient 12 would be expected to be injectable and therefore identical to the instantly claimed composition.
Claim 20 recites the pharmaceutical composition in the form of an aerosol or an injectable solution. The BRI of this claim is still directed towards the natural product without significantly more, because both plasma and human blood are injectable solutions (See, for example, Duncan J. On Re-Infusion of Blood in Primary and Other Amputations. Trans Med Chir Soc Edinb. 1886;5:42-48. PMID: 29584250; PMCID: PMC5535545).
Regarding claim 23, the claim is directed towards a method for blocking the entry of SARS-CoV-2 in an ACE2-expressing cell, the method comprising contacting the cell and/or the virus with an effective amount of the antibody or antigen-binding fragment of claim 1. This claim is directed towards a natural phenomenon without significantly more because, as described above, the instant antibody is a natural product, and the method as described would occur in the human patient from which the antibody was obtained. As described in Suthar, Mehul S., et al. "Rapid generation of neutralizing antibody responses in COVID-19 patients." Cell Reports Medicine 1.3 (2020), in a human patient the SARS-CoV-2 RBD interacts with the ACE2 receptor for cellular attachment (Introduction ¶1). In an acutely infected COVID-19 patients, the immune system mounts an immunoglobulin response against the RBD of the SARS-CoV-2 spike protein (Results, ¶1, Table 1). The antibodies developed in the human during the response including neutralizing antibodies binding to RBD, which block the infection of ACE2 expressing cells (demonstrated by Suthar et. al. ex vivo (Fig. 2), but would occur during the immune system response in vivo). Suthar et. al. demonstrate that the neutralizing antibodies correlate with progression of the SARS-CoV-2 infection (Fig. 3), showing that the contacting occurring in the human body as a natural phenomenon of the immune response is sufficient to block the entry of SARS-CoV-2 into a ACE2 expressing cell as claimed. Therefore, claim 23 is directed towards the natural phenomenon of the immune response of patient 12 to the COVID-19 virus without significantly more. There are no additional limitations required by the claim beyond the natural phenomenon of the naturally occurring antibody contacting the cell and/or virus.
Thus, instant claims 1-4, 6-9, 11-12, 16-20, and 23 recite a judicial exception and claim a composition (1-9, 11-12, 16-20) or a natural phenomenon (claim 23) for which the judicial exception is not integrated into a practical application, and no elements that amount to significantly more than the judicial exception are required, and the claims are ineligible subject matter under 35 U.S.C. §101.
Regarding claims 21-22 and 25, the claims are excluded from this rejection because although they recite the natural product, the claims are directed towards methods comprising administering the antibody and therefore are integrated into a practical application of a particular treatment or prophylaxis for a disease (MPEP § 2106.04(d)(2)). Claim 5 is excluded because as described in the Formal Matters and Specification objections above, the specification teaches that the complete VL of the naturally occurring antibody is one residue different in FR4 than SEQ ID NO: 48, and therefore there is no evidence that the antibody comprising SEQ ID NO: 48 in the FR4 as claimed is a natural product.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1, 4, 7, and 16-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2022143815 A1 to Sun et. al. effectively filed 31 December 2020.
Sun et. al. teaches a neutralizing antibody against an epitope of a receptor binding domain of SARS-CoV-2 which blocks the interaction between SARS-CoV-2 RBD and ACE2 thereby preventing and controlling SARS-CoV02 infections and reducing the occurrence of drug resistance. One of the antibodies comprises a VH/VL pair of SEQ ID NO: 4 and SEQ ID NO: 16, which comprise CDRs at least 70% identical to each of the CDRs of instant SEQ ID NOs: 23, 28, 33 and 36, 39, 41:
Query Match 58.8%; Score 77; Length 121;
Best Local Similarity 22.9%;
Matches 19; Conservative 1; Mismatches 3; Indels 60; Gaps 2;
Qy 1 GYTFSSY-------------------SPYNGN---------------------------- 13
||||||: ||||||
Db 26 GYTFSSFGISWFRQAPGQGLQWMGWISPYNGNTKYAQKLQGRVTMTTHTSTTTAYTELRS 85
Qy 14 -------------DLELGGGFDY 23
| || | |||
Db 86 LRSDDTAVYYCARDWELLGRFDY 108
Query Match 77.9%; Score 129.3; Length 110;
Best Local Similarity 35.9%;
Matches 28; Conservative 3; Mismatches 0; Indels 47; Gaps 2;
Qy 1 TGTSSDVGSYNLVS---------------EGTKRPS------------------------ 21
||||||||:||||| ||:||||
Db 23 TGTSSDVGNYNLVSWYQHHPGKAPELMIYEGSKRPSGVSNRFSASKSGNTASLTISGLQA 82
Qy 22 --------CSYAGNSTWV 31
|||||:||||
Db 83 EDEADYYCCSYAGSSTWV 100
Regarding claim 4, framework region 3 of SEQ ID NO: 16 is at least 50% identical to instant SEQ ID NO: 55 as shown below:
PAT. SEQ. LOC: SEQ ID NO 16
ALIGN
ALIGNMENT FROM L-NUMBER L7
Query Length: 32; Sequence Length: 110;
Score: 65.5 bits (158), 96.6% of highest possible score 67.8;
Expect value: 1.488e-9;
Identities: 31 / 32 (96.9%); Positives: 31 / 32 (96.9%);
Query Identity: 96.9%; Query Coverage: 100.0%;
Subject Identity: 28.2%; Subject Coverage: 29.1%;
Alignment Length: 32;
Q: 1 GVSNRFSGSKSGNTASLTISGLQAEDEADYYC 32
||||||| ||||||||||||||||||||||||
S: 59 GVSNRFSASKSGNTASLTISGLQAEDEADYYC 90
Regarding claim 7, framework region 3 of SEQ ID NO: 4 is at least 50% identical to instant SEQ ID NO: 59 as shown below:
PAT. SEQ. LOC: SEQ ID NO 4
ALIGN
ALIGNMENT FROM L-NUMBER L15
Query Length: 41; Sequence Length: 121;
Score: 74.7 bits (182), 85.5% of highest possible score 87.4;
Expect value: 2.435e-12;
Identities: 36 / 41 (87.8%); Positives: 36 / 41 (87.8%);
Query Identity: 87.8%; Query Coverage: 100.0%;
Subject Identity: 29.8%; Subject Coverage: 33.9%;
Alignment Length: 41;
Q: 1 TKYPQKFQGRVTMTTDTSTNTAYMELRSLRSDDTAVYYCAR 41
||| || |||||||| ||| ||| |||||||||||||||||
S: 58 TKYAQKLQGRVTMTTHTSTTTAYTELRSLRSDDTAVYYCAR 98
Regarding claim 16, one embodiment of the invention is a chimeric antigen receptor comprising the antibody (p. 3 bottom ¶) and an antibody-drug conjugate (p. 4 ¶3-5).
Regarding claim 17, Sun et. al. teaches a nucleic acid encoding the antibody (p. 5 middle; p. 7 ¶8). Regarding claim 18, Sun et. al. teaches the nucleic acid cloned into a host cell (p. 8, 5th ¶ from the bottom).
Regarding claim 19, Sun et. al. teaches the antibody in pharmaceutical composition with a carrier or excipient (p. 9 ¶10). Regarding claim 20, Sun et. al. teaches the composition can be formulated for injection (p. 9 ¶10).
Regarding claims 21-23, Sun et. al. teaches that the pharmaceutical composition is for preventing and/or treating a SARS-CoV-2 infection (p. 4, see middle “eleventh aspect” section) and the method comprises administering the antibody or antibody-drug conjugate, or CAR-T cells expressing the antibody, or a combination thereof. Sun et. al. teaches that the different antibodies are administered with additional antibodies targeting other epitopes to have a synergistic effect and avoid drug resistance problem formed by continuous viral mutation (p. 9 3rd ¶ from the bottom, p. 16 Example 2.6)
Claims 1 and 16-23 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by WO2021229561 to Noy-Porat et. al. effectively filed 14 May 2020.
Noy-Porat et. al. teach an anti-SARS-CoV-2 antibody comprising a VH and VL SEQ ID NOs: 29 and 30 comprising CDRs at least 70% identical to instant CDRs SEQ ID NOs: 1, 6, 11 and 14, 17, 19 as shown below:
Query Match 66.4%; Score 73; Length 118;
Best Local Similarity 23.2%;
Matches 19; Conservative 2; Mismatches 1; Indels 60; Gaps 2;
Qy 1 GITVSSN-------------------YSGGS----------------------------- 12
|:||||| |||||
Db 26 GVTVSSNYMNWVRQTPGKGLEWVSVIYSGGSTYYADSVKGRFTISRDNSKNTLYLQMNSL 85
Qy 13 ------------DLEMAGAFDI 22
|| :||||||
Db 86 RAEDTAVYYCARDLAVAGAFDI 107
Query Match 51.2%; Score 65.5; DB 1; Length 108;
Best Local Similarity 31.9%;
Matches 23; Conservative 1; Mismatches 1; Indels 47; Gaps 2;
Qy 1 RASQSVSSSYLA---------------GASSRAT-------------------------- 19
|||||:|||||| ||| |||
Db 24 RASQSISSSYLAWYQQKPGQAPRLLIYGASIRATGIPDRFSGSGSGTDFTLTISRLEPED 83
Qy 20 ------QQYGSS 25
||||||
Db 84 FAVYFCQQYGSS 95
Regarding claim 16, Noy-Porat et. al. teaches an immunoconjugate comprising the antibody of fragment thereof (p. 84, second ¶ from the bottom).
Regarding claim 17 and 18, Noy-Porat et. al. teaches an expression vector comprising a nucleic acid molecule encoding the antibody and host cells transfected with the nucleic acids (p. 84 ¶2-4).
Regarding claim 19, Noy-Porat et. al. teaches a pharmaceutical composition comprising an excipient (p. 85 ¶5).
Regarding claim 20, Noy-Porat et. al. teaches that the composition was intravenously injected (p. 111 ¶3) and therefore the composition reads on injectable solution.
Regarding claims 21-23, Noy Porat et. al. teaches a method comprising administering the antibodies of the invention to K18-hACE2 mouse model of SARS-CoV-2 (Example 7 p. 108) and teaches a method of prophylaxis, treatment, or amelioration of SARS-CoV-2 infection (p. 89) comprising administering the antibody to a subject prior to or after disease onset (p. 89).
Regarding claim 25, Noy Porat et. al. teaches that the SARS-CoV-2 antibody of the invention may be administered with an additional therapeutic agent wherein the additional agent is an additional antibody, such as the combined use of at least two antibodies of the invention (p. 85 )
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 25 is rejected under 35 U.S.C. 103 as being unpatentable over WO2022143815 A1 to Sun et. al. effectively filed 31 December 2020.
The teachings of Sun et. al. in regards to claims 1 and 21 are in the 102 rejection above.
Sun et. al. does not explicitly teach a method of treatment comprising administering the antibody with an additional SARS-CoV-2 antibody.
Sun et. al. teaches that the pharmaceutical composition is for preventing and/or treating a SARS-CoV-2 infection (p. 4, see middle “eleventh aspect” section) and the method comprises administering the antibody or antibody-drug conjugate, or CAR-T cells expressing the antibody, or a combination thereof. Sun et. al. teaches that the different antibodies are administered with additional antibodies targeting other epitopes to have a synergistic effect and avoid drug resistance problem formed by continuous viral mutation (p. 9 3rd ¶ from the bottom, p. 16 Example 2.6).
It would have been obvious for a person of ordinary skill in the art, before the effective filing date, to administer the antibody of SEQ ID NO: 4 and SEQ ID NO: 16 as taught by Sun et. al. in combination with another anti-SARS-CoV-2 antibody in order to have a synergistic effect and avoid drug resistance as taught by Sun et. al. This would have a reasonable expectation of success because Sun et. al. teaches that the antibodies of the invention that target different epitopes can be used in a drug cocktail.
Conclusion
No claims are allowed.
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/KATHLEEN CUNNINGCHEN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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