DETAILED ACTION
Non-Final Rejection
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election of Group I claims 1-23 and 25-28 in the reply filed on 02/02/2026 in response to Restriction and Election requirement, and additionally response to sequence compliance requirement filed on 05/26/2026 indicating SEQ ID NO for elected species is acknowledged.
Election of Species for Group I:
Applicant elected antibody species BG10-19, identified by:
" Heavy chain variable region: HCBG10-19 (SEQ ID NO: 276, within SEQ ID NOs: 185- 368).
" Light chain variable region: LCBG10-19 (SEQ ID NO: 368, within SEQ ID NOs: 185- 368)
The corresponding CDR3 sequences (SEQ ID NO: 92) for BG10-19 are also encompassed within SEQ ID NOs: 1-184.
Applicant indicated that claims readable on elected antibody BG10-19 include claim 1.
Applicant’s argument regarding the lack unity of invention over the shared technical features of an antibody or antigen binding fragment thereof, inter alia, that binds to the SARS-CoV-2 RBD and/or SARS-CoV-2 spike trimer, and these shared technical features do not represent a contribution over the prior art of US 10,787,501B1 to Babb et al 2020 is considered but not found persuasive. Because under BRI the claim reads on an antibody that binds to SARS-CoV-2 spike protein RBD or neutralize SARS-CoV-2 virus and Babb et al 2020 taught the claimed genus of an antibody.
Because applicant did not distinctly and specifically point out the supposed errors other than the argument as addressed above in the restriction requirement, the election has been treated as an election without traverse (MPEP § 818.01(a)).
Status of Claims
3. Claims 1-35 filed on 05/26/2026 are pending.
4. Withdrawn Claims: Claim 24 (Group II) claims 29-34 (Group III) and claim 35 (Group IV) are withdrawn from examination being non-elected groups of invention due to Restriction/Election. Claims 6-11, and 17-23 (Group I) are withdrawn by the applicant.
5. Claims 1-5, 12-16 and 25-28 the elected Group I claims are under examination.
Priority
6. This application is a 371 of PCT/US21/65737 and claims the benefit of U.S. Provisional Application No. 63/132,695 filed December 31, 2020, and 63/155,220 filed March 1, 2021.
Information Disclosure Statement
7. The information disclosure statement (IDS) submitted on 06/28/2023 and 02/05/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
8. 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.
The instant specification list more than 120 references on page numbers 171 through 184.
CRF Statement for Sequence Listing
9. The response filed by the applicant (05/26/2026) for sequence compliance requirement office action 03/27/2026 is entered.
Specification
10. The substitute specification filed on 05/26/2026 for amendment /modification for including the SEQ ID NOs in Tables 2A, 2B and 7 is entered as a response filed by the applicant (05/26/2026) for sequence compliance requirement office action 03/27/2026.
11. The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Rejections - 35 USC § 112
12. The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-5, 12-16 and 25-28 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.
Claims 1-5, 12-16 and 25-28 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being incomplete for omitting essential structural cooperative relationships of elements, such omission amounting to a gap between the necessary structural connections. See MPEP § 2172.01. The omitted structural cooperative relationships are specific assignment of CDR3 heavy chain and light chain sequences (SEQ ID NO) to each of the recited Markush species BG1-1, BG1-3 to BG1-28, BG4-1 to BG4-27, BG7-1 to BG7-7, BG7-9 to BG7-20, and BG10-1 to BG10-19. The applicant has recited the antibody as group (e.g. BG1-3 to BG1-28). The claim has recited the sequences as group of sequences (SEQ ID NOS: 1-184) without showing specific assignment for each elected species of the recited specific SEQ ID NO. Therefore, it is ambiguous and not clear to one of the ordinary skills that which SEQ ID NO reciting the amino acid sequence structure corresponds to the recited different species of the Markush group of antibodies (e.g. BG1-1 antibody, it is not clear which SEQ ID NOs corresponds to the structure of BG1-1). The omitted specific assignment of structural (SEQ ID NO) cooperative relationships of antibody is critical or essential to make a practice the claimed invention. The claims fail to define the metes and bounds of the critical structure of the CDR3 and Heavy and light chain sequence. The claim as recites the antibody species in groups and SEQ ID NOs as grouped raises doubt and confusion whether the sequences can be used in different combination?
Secondly, the claims recite a limitation, “a complementarity-determining region 3 (CDR3) heavy chain and light chain pair that shares at least 90% identity with the heavy chain and/or light chain of a pair selected from the group consisting of:”. It is ambiguous whether the 90% identity (10% differences) are directed to the CDR3 or additionally includes CDR1, CDR 2 and constant regions of heavy chain and/or light chain. Applicant is required to amend the claims for clarity.
Where possible, claims are to be complete in themselves. See, MPEP 2173, MPEP 2173(s). The applicant has not recited the reference to the figures or tables in specification, but the applicant has put the unnecessary burden on the examiner (and ordinary skills) to figure out which SEQ ID NO corresponds to the recited antibody by referring to the specification.
To overcome the rejection, the applicant is required to pair each recited antibody with corresponding specific heavy and light chain SEQ ID NOs and thereby enhance specificity and clarity of the claims. Applicant is required to indicate the support for the claim amendments in the specification.
Claim Rejections - 35 USC § 112 (Written Description)
13. 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.
This is a Written Description Rejection.
Claims 1-5, 12-16 and 25-28 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.
According to the specification, in the preferred embodiments, the antibody is a “monoclonal antibody”, refers to a single antibody produced by screening B cell and recombinant DNA technology (See para [0090]) and the antibody bind or recognize the SARS-CoV-2 spike protein receptor-binding domain (RBD), and can block the virus from attaching to ACE-2 on human cells and thus neutralize the SARS-CoV-2 virus. The antibodies are obtained from B cells of people who recovered from COVID-19 (See, para [0022], and other parts of specification). In certain embodiments, a CDR3 of VH and VL requires only 90% identity (allows 10% amino acid difference) of amino acid to the antibodies to SARS-CoV-2 virus (See, para [0008]).
Therefore, the scope of claim 1 and dependent claims 4-5, 12-16 and 25-28 is generic (very broad) because the claim recites a genus of an antibody and a monoclonal antibody comprising 10% amino acid variation (90% amino acid identity). The claim 1 recites limitations that are generic, and the specification does not have support commensurate with the full scope of the claimed invention, “an antibody” or “a monoclonal antibody, or an antigen binding fragment thereof, which binds to and neutralize SARS-COV-2 spike protein with at least 90% sequence identity to the CDR-3 VH and VL an antibody. The claim 1 allows up to 10% amino acid substitutions introducing variant species of claimed antibody, a monoclonal antibody or antibody.
The claims 1-5, 12-16 and 25-28 are directed to a functional limitation “binding to SARS-COV-2 the SARS-CoV- 2 receptor-binding domain (RBD) and/or SARS-CoV-2 spike trimer (claims 1-5, 12-16) and neutralizing SARS-COV-2 virus (claims 25-28).
It has been well known in the art that minor structural differences even among structurally related compounds or compositions can result in substantially different biological or pharmacological activities. It is known in the art that the substitution of amino acids within the protein sequence may cause the loss of function of the protein. Thus, the 10% variation (90% identity) resulting in “variant” antibody or fragments or fragments thereof encompassed by the instant claim 1 may or may not be effective in achieving the claimed function of binding to the SARS-CoV-2 virus spike RBD (BRI also reads on variant SARS CoV-2 viruses) or effectively neutralizing SARS-CoV-2 viruses (instant claims 25-2) or binding affinities similar to the antibodies that has wild type and or recombinant amino acid sequences (without mutations/substitution/variations) in the claimed CDR-3 VH/VL. Specifically in relation to antibody CDRs, it should be pointed out that it is well established in the art that the formation of an intact antigen-binding site requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three different complementarity determining regions, CDR1, 2 and 3, which provide the majority of the contact residues for the binding of the antibody to its target epitope. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al 2001, Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: ncbi.nlm.nih.gov/books/NBK27144/. See entire article). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al 1982, Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982;79(6):1979-1983, see entire article, particularly the abstract and the middle of the left column of page 1982).
The instant specification does not have written description support by reduction to practice of example(s) showing that that the applicant possesses the claimed recombinant CDR-3 VH and VL antibody variants with 90% amino acid identity to the wildtype antibody VH+VL or six CDR sequences CDR H1-H3 and CDR L1-L3 that comprise 10% variation in amino acid sequence that is required to be satisfied through sufficient description of a representative number of species by actual reduction to practice showing similar binding to spike protein and binding or neutralizing efficacy of a SARS-CoV-2 coronavirus. Many different variants of recombinant antibody or the antigen binding fragment thereof are possible and can be envisioned by the ordinary skills given 10% amino acid variation (90% identity).
To satisfy the written description requirement, a patent 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. See, e.g., Moba, B.V. v. Diamond Automation, Inc., 325 F.3d 1306, 1319, 66 USPQ2d 1429, 1438 (Fed. Cir. 2003); Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 USPQ2d at 1116. 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, reduction to drawings, or 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 inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021). See MPEP 2163 “Written Description Guidelines”.
The Federal Circuit has clarified the application of the written description requirement to inventions in the field of biotechnology. See University of California v. Eli Lilly and Co., 119 F.3d 1559, 1568,43 USPQ2d l398, 1406 (Fed. Cir. 1997). The Court stated that a written description of an invention requires a precise definition, one that defines the structural features of the chemical genus that distinguishes it from other chemical structures. A definition by function does not suffice to define the genus because it is only an indication of what the genus does, rather than what it is. Further, the Court held that to adequately describe a claimed genus, an applicant must describe a representative number of species of the claimed genus, and that one of skill in the art should be able to “visualize or recognize the identity of the members of the genus.”
Amgen Inc. vs Sanofi (2017-1480, Fed Cir, 2017) states that "an adequate written description must contain enough information about the actual makeup of the claim products - a precise definition such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other material," which may be present in "function "terminology "when the art has established a correlation between structure and function" (page 17,1st paragraph).
Therefore, the ordinary skill in the art is not reasonably convinced that the applicant and inventors at the time the application was filed, had possession of the full scope of claimed invention as claimed in claim 1 and dependent claims (claims 2-5, 12-16 and 25-28). Because there is no variant species of antibody or insufficient representative species and/or identifying characteristics to place applicant in possession of the generic scope of the claimed invention directed to a recombinant antibody comprising amino acid sequence with 90% identity (comprising 10% amino acid variation) and has a function of binding to spike protein of SARS-CoV-2 virus and neutralizing of SARS-CoV-2 virus.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
14. 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.
This is a scope of enablement rejection.
Claims 1-5, 12-16 and 25-28 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 the elected species antibody BG10-19 comprising the elected sequences SEQ ID NO: 276, VH of BG10-19, SEQ ID NO: 368, VH of BG10-19 and SEQ ID NO: 92, CDR3 of BG10-19 does not reasonably provide enablement for an antibody comprising a complementarity-determining region 3 (CDR3) heavy chain and light chain pair that shares at least 90% identity . The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to how make and use the invention commensurate in scope with these claims. The specification is not enabling the claimed antibody species that are generated by using a complementarity-determining region 3 (CDR3) heavy chain and light chain pair that shares at least 90% identity.
The legal considerations that govern enablement determinations pertaining to undue experimentation have been clearly set forth. Enzo Biochem, Inc., 52 U.S.P.Q.2d 1129 (C.A.F.C. 1999). In re Wands, 8 U.S.P.Q.2d 1400 (C.A.F.C. 1988). Ex parte Forman 230 U.S.P.Q. 546 (PTO Bd. Pat. App. Int., 1986). The courts concluded that several factual inquiries should be considered when making such assessments including the nature of the invention, the state of the prior art, the breadth of the claims, the amount of guidance in the specification, the presence or absence of working examples, the predictability or unpredictability of the art, and the quantity of experimentation necessary. In re Rainer, 52 C.C.P.A. 1593, 347 F.2d 574, 146 U.S.P.Q. 218 (1965). The disclosure fails to provide adequate guidance pertaining to a number of these considerations as follows:
Nature of the invention. The claims 1-5, 12-16 and 25-28 are directed to an antibody or an antigen-binding fragment thereof that binds to SARS-CoV-2 spike protein RBD or neutralize against SARS-coronavirus 2 (SARS-CoV2), wherein the antibody comprises CDR-3 VH and VL sequence with 90% identity (reads on 10% variation). The claim recites a functional limitation of binding or neutralizing of SARS-coronavirus 2 (SARS-CoV-2) virus without providing a definite substitution, insertion or deletion of amino acids in the CDR3 VH and VL sequence.
State of the prior art: The prior art is unpredictable because of the functional limitation of binding of the claimed genus of antibody comprising CDR3 VH and VL with 90% identity to the claimed antibody that bind to SARS-CoV-2 virus spike or neutralize SARS-CoV-2 virus. The functional limitation “binding” or “neutralizing” is not reasonably possible to achieve at a desired higher efficacy to the SARS-CoV-2 virus due to 10% level of variability and thousands of possible envisioned species generated due to variability in the CD3 VH and VL sequence. See, 35 USC 112(b) and 112(a) written description rejection above. The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity which is characteristic of the parent immunoglobulin (Janeway et al 2001, Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001. The structure of a typical antibody molecule. Available from: ncbi.nlm.nih.gov/books/NBK27144/. See entire article). It is also known that single amino acid changes in a CDR can abrogate the antigen binding function of an antibody (Rudikoff et al 1982, Single amino acid substitution altering antigen-binding specificity. Proc Natl Acad Sci U S A. 1982;79(6):1979-1983, see entire article, particularly the abstract and the middle of the left column of page 1982).
Working Examples. Reduction to practice is not achieved as the specification do not disclose even a single working example of an antibody with 90% identity with CDR3 VH and VL or neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) 90% identity with CDR3 VH and VL or based on CDR3 VH and VL with 90% identity.
The claims assigned a functional limitation of binding or neutralizing of the claimed variant antibody against SARS-coronavirus 2 (SARS-CoV2) or but did not provide the working example(s) reduced to practice showing possession of “how to make and use” for claims 1-5, 12-16 and 25-28.
The amount of experimentation necessary. The quantity of experimentation needed to make or use the invention based on the content of the disclosure places undue experimentation burden on the ordinary skills in the art. One skilled in the art would require performing many permutations and combinations of amino acid sequence variations in the CDR3 VH and VL based on broad generic claim 1 that comprise an antibody genus with a function of binding or neutralization of SARS-coronavirus 2 (SARS-CoV2) virus. It would require undue experimentation to cover the breadth of the claims that requires to achieve the function of binding or neutralization to enable the full scope of the claims 1-5, 12-16 and 25-28 for the claimed antibody activity to be reasonably effective for intended therapeutic applications in the SARS-CoV-2 virus infected subjects or diagnostic test sensitivity. The ordinary skills in the art would be burdened with planning, engineering the claimed CDR3 VH and VL, executing the optimization experiments and developing many thousands of antibody species to arrive at the claimed inventions. Many numbers of experiments will be required to generate statistically significant data to encompass the full scope and breadth of the claimed invention. There will be undue experimentation burden on the ordinary skills in the art.
The level of one of ordinary skill. The level of ordinary skills required is very high with a PhD degree or and many years of experience in antibody engineering research field.
Level of predictability in the art. One skilled in the art would require performing many permutations and combinations of amino acid sequence variations in the CDR3 VH and VL to arrive at the inventions of broad generic claims that comprise an antibody for the claimed function as recited supra and is unpredictable to achieve. For the reasons discussed above in the written description (112(a) and indefinite rejection (112(b) (see above), it would have required undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice the full scope of the invention claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skills which is high, no working examples provided for the variant antibody of claims 1-5, 12-16 and 25-28 and scarcity of guidance in the specification, and the unpredictable nature of the art. The enablement inquiry for claims that include functional requirements “binding” and or “neutralizing activity” and there is unpredictability of the art and guidance in specification fall short is addressed in “Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 1086 (Fed. Cir. 2021)”. The claimed scope of claims 1-5, 12-16 and 25-28 is highly unpredictable to reduce to the practice.
Breadth of claims. The claims 1-5, 12-16 and 25-28 are directed to the genus of antibody binding SARS-CoV-2 spike protein or neutralizing SARS-CoV-2 virus comprising CDR-3 VH and VL with 90% identity (10% variation). The claims assigned functional limitations binding to the spike protein of SARS-CoV-2 spike RBD or neutralizing SARS-CoV-2 virus but did not provide the working example(s) reduced to practice showing possession of “how to make and use” the variant antibody with similarly achieved claimed function. It would require undue experimentation to cover the breadth of the claims to enable at full scope in absence of support for the subject matter in the instant specification. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to how make and use the invention commensurate in scope with these claims. The specification is not enabling the claimed antibody species that are generated by using the CDR-3 VH and VL with 90% amino acid identity (reads on 10% variation).
Additionally, in the recently decided Amgen v. Sanofi (590 U.S. 594; 143 S.Ct. 1243 May 18, 2023) Supreme Court decision addressing enablement, the Court held that enablement of an unpredictably broad functional claim (e.g. functionally specific analogous antibodies or the instant claimed neutralizing antibody that specifically bind or neutralize SARS-CoV-2 virus) requires sufficient disclosure in light of the state of the prior art as to how to enable the making (e.g. protocols) and use for the full range of the claimed invention without unreasonable or undue experimentation.
The amount of direction provided by the inventor: The specification does not provide guidance regarding “how to make and use” the variant CDR3 VH and VL (See, 112(a) written description and 112(b) above) of the claimed composition of claims 1-5, 12-16 and 25-28 by reduction to practice by working example in the specification showing enablement for claims 1-5, 12-16 and 25-28 showing achievement of a claimed function of binding and or neutralizing SARS-coronavirus 2 (SARS-CoV2) with an antibody comprising CDR3 VH and VL amino acid sequence with 90% identity.
For the reasons discussed above, it would have required an undue experimentation for one skilled in the art before the effective filing date of the claimed invention to practice over the full scope of the invention claimed. This is particularly true given the nature of the invention, the state of the prior art, the breadth of the claims, the amount of experimentation necessary, the level of skill which is high, the working examples provided and scarcity of guidance in the specification, and the unpredictable nature of the art. The enablement inquiry for claims that include functional requirements and there is unpredictability of the art and guidance in specification fall short is addressed in “Amgen v. Sanofi, Aventisub LLC, 987 F.3d 1080, 1086 (Fed. Cir. 2021)”.
Given the breadth of the claims 1-5, 12-16 and 25-28., the lack of guidance in the specification, and the lack of predictability of the art, it would require undue experimentation and places undue burden on one skilled in the art to make and use/practice the claimed method to the full scope the claimed inventions in claims 1-5, 12-16 and 25-28 and therefore consequently raise doubt as to the enablement of full scope of the claims.
Claim Rejections - 35 USC § 112 (Improper Markush Grouping)
15. Improper Markush Grouping Rejection.
The Claims 1-5, 12-16 and 25-28 are rejected on the basis that it contains an improper Markush grouping of alternatives.
See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
In the instant claims 1-5, 12-16 and 25-28 the Markush grouping of the claimed antibody are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons: the claims recite discrete antibody binding CDR3 VH and VL domains that do not all share significant structural similarity. Even minor changes in the amino acid sequences of the heavy and light variable regions, particularly in the CDRs, may dramatically affect antigen-binding function as evidenced by Rudikoff 1982 (Proc Natl Acad Sci USA 1982 Vol 79, page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (See, entire article).
The following exemplified sequences constitute the CDR3 regions of claim 1 Markush species (specification filed on 05/26/2026 table 2A) which share no significant structural similarity:
Heavy Chain CDR3
SEQ ID NO:01, CAKQWLANWFDPW
SEQ ID NO:27, CAKDLGYSYGSEIFDYW
SEQ ID NO:92, CARTQWGYNYGSHFFYMDVW
SEQ ID NO:74, CAKSNSSGLTPFDHW
SEQ ID NO:62, CARDLTYYGSNGYTNW
Light Chain CDR3
SEQ ID NO:074, CQQSESSPYTF
SEQ ID NO:119, CQQSYSTPVF
SEQ ID NO:174, CQAWDSSTGVF
SEQ ID NO:166, CQQSYSNPFTF
SEQ ID NO:154, CQQYNTYFWTF
Although only CDR3 amino acid sequences are shown above as an example, an artisan would understand that the sequence differences in the CDRs overall would amount to structural differences in the antibody binding region as a whole, and therefore there would be no structural similarity between the antibodies leading to be functionally equivalent (e.g. binding to SARS CoV-2 Spike RBD and or neutralizing SARS CoV-2 virus) and to their common use.
In the instant case, the instant claim 1 recites an antibody CDR3 VH and VL with at least 90% identity (10% variation) to achieve a function of binding to SARS-CoV-2 virus Spike RBD, and the instant claims 25-28 to achieve a function of neutralizing of SARS-coronavirus 2 (SARS-CoV2). The specific amino acid substitutions or deletions or insertions that can amount to 10% variation to the CDR3 VH and VL sequence is not recited in the claims or in the specification. The structure of the variant CDR3 VH and VL comprising variability is not commensurate with the claimed genus of antibody that can comprise thousands of envisioned species by the ordinary skills.
Additionally, claims 4-5 recite additional improper Markush groups of antibodies comprising CDR3 VH and VL.
MPEP 803.02 provides guidance on the analysis of a proper Markush group. Members of a proper Markush group are disclosed in the specification to possess at least one property in common which is mainly responsible for their function in the claimed relationship, and it is clear from their very nature or from the prior art that all of them possess this property. The MPEP further provides that in the members of a proper Markush group there should be (1) a common utility, and (2) a substantial structural feature essential to that utility.
In response to this rejection, Applicant should either amend the claim(s) to recite only individual species or grouping of species that share a substantial structural feature along with a specific defined sequence for the structure of the CDR3 VH as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims(s) in fact share a substantial structural feature as well as a common use that flows from the substantial structural feature.
The dependent claims 2-5, 12-16 and 25-28 are rejected for failing to resolve the improper Markush grouping.
To overcome this rejection, the Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Interpretation
16. The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art.
Claim 1: The claim 1 is interpreted to be directed to an antibody or a monoclonal antibody or antigen binding fragment thereof that binds to the SARS-CoV- 2 receptor-binding domain (RBD) and/or SARS-CoV-2 spike trimer comprising: a complementarity-determining region 3 (CDR3) heavy chain and light chain pair that shares at least 90% identity with the heavy chain and/or light chain of a pair selected from the group consisting of: BG1-1, BG1-3 to BG1-28, BG4-1 to BG4-27, BG7-1 to BG7-7, BG7-9 to BG7-20, and BG10-1 to BG10-19 (SEQ ID NOS: 1-184); or a heavy chain and light chain pair that shares at least 90% identity with the heavy chain and/or light chain of a pair selected from the group consisting of: BG1-1, BG1-3 to BG1-28, BG4- 1 to BG4-27, BG7-1 to BG7-7, BG7-9 to BG7-20, and BG10-1 to BG10-19 (SEQ ID NOS: 185- 368).
The claimed antibody or a monoclonal antibody is interpreted to be directed to an isolated antibody or isolated monoclonal antibody or recombinantly derived from a single memory B cell of obtained from a SARS CoV-2 survivor subjects and binds to SARS-CoV-2 Spike RBD and or neutralize SARS-CoV-2 virus. An antibody that is isolated from SARS-CoV-2 survivors (a monoclonal antibody) is also interpreted to comprise wild type CDR3 HV and VL sequence without amino acid substitution or swapping of CDRs among antibodies without any modifications to generate an recombinant antibody or monoclonal antibody (See, instant specification, para [0148], para [0090]).
Claim Rejections - 35 USC § 101
17. 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.
Claims 1-5, and 12-16 are rejected under 35 U.S.C. 101 because according to the broadest reasonable interpretation (BRI) in view of the instant specification, the claim 1 (and dependent claims 2-5 and 12-16) are interpreted to be directed to a product of nature derived from human that survived SARS CoV-2 infectionan antibody, a monoclonal antibody or a recombinant antibody that is recombinantly derived from a single memory B cell of obtained from SARS CoV-2 virus infection survivor people. Some naturally isolated antibodies from SARS-CoV-2 virus infection survived humans bind to SARS-CoV-2 RBD or spike trimer. The claim 1 recites an alternative limitation, “An antibody or antigen binding fragment thereof” that binds to the SARS-CoV- 2 receptor-binding domain (RBD) and/or SARS-CoV-2 spike trimer comprising, inter alia, BG10-19. The applicant isolated 92 from B-cells and were tested (See, instant specification, para [0148], claim 1). The term "monoclonal antibody" also refers to an antibody derived from a clonal population of antibody-producing cells (e.g., B lymphocytes or B cells) which is homogeneous in structure and antigen specificity. As used in the specification, the term "monoclonal antibody" refers to a single antibody produced by any means, such as recombinant DNA technology (See, instant specification). A monoclonal antibody is produced by the single memory B cell and the monoclonal antibody bind to spike protein of SARS-CoV-2 virus and or neutralize SARS-CoV-2 virus. The monoclonal antibody is also interpreted to comprise wild type HV and VL sequence without amino acid substitution to generate a recombinant monoclonal antibody. The claim 1 thus encompasses antibodies that are structurally identical to naturally occurring antibodies. Because there is no difference in characteristics (structural, functional, or otherwise) between the claimed and naturally occurring antibodies for at least some of the embodiments encompassed by the claim, the claimed antibodies do not have markedly different characteristics, and thus are a “product of nature” exception. The added limitations of the rejected dependent claims 2-5, and 12-16 are commensurate within the scope of isolated antibodies that occur naturally in SARS-CoV-2 virus infection survivors.
Step 1: According to MPEP § 2106, the claimed invention must be to one of the four statutory categories. According to 35 U.S.C. 101 the eligibility test, the claim 1 (and dependent claims 2-5 and 12-16) are directed to a statutory category, e.g. composition of matter (the claimed antibody with a function of binding to a SARS-CoV-2 virus spike protein and neutralization of SARS-CoV-2 virus), therefore, statutory category eligibility, Step 1: Yes.
Step 2: As described in the instant specification and the prior art Cao et al 2020, Zost et al 2020, and Liu et al 2020 recited below the claimed genus of antibody, monoclonal antibody or recombinant monoclonal antibody is produced by a human single B cell (plasma cell) in response to a SARS-CoV-2 virus infection and can be termed as a monoclonal antibody which naturally comprise the antigen binding fragment, Fc, VH and VL chains. The antibody has a function of binding to spike protein (surface protein of a coronavirus) and neutralizing a SARS-CoV-2 virus. The claimed recombinant monoclonal antibodies uses the VL and VL sequences from the B cell and does not have markedly different characteristics or function from what exist in nature or human, and thus is “a product of nature” exception, Step 2A: Prong 1- Yes: claim 1 (and dependent claims) recite a “judicial exception” a product of nature.
The claim 1 (and dependent claims 2-5, and 12-16) fails to integrate (e.g. composition of matter-the claimed antibody, monoclonal antibody with a function of binding to a SARS-CoV-2 virus spike protein) the judicial exception into a practical application (e.g method of treatment, diagnostic assay or purification) or contain additional elements that result in a “markedly different” antibody as compared to the natural counterpart, Step 2A: Prong 2-No.
The claim 1 (and dependent claims 2-5 and 12-16) do not include additional elements that are sufficient to amount to significantly more to the claimed composition of matter an antibody or a monoclonal antibody (a genus) (than the judicial exception because the claims recite an antibody or a monoclonal antibody and additional antibody species in the genus, as to constitute an “inventive concept” (e.g. improvement) Step 2B: No.
Babb et al 2020 (US10787501B1). Babb et al 2020 teaches an isolated antibody or antigen-binding fragment thereof that binds a SARS-CoV-2 spike protein RBD and neutralizing SARS-CoV-2 virus and methods of using such antibodies and fragments for treating or preventing viral infections (See, abstract, claim 1 and entire prior art).
Cao et al 2020 teaches SARS CoV-2 spike RBD domain binding neutralizing and non-neutralizing monoclonal antibodies obtained from a B cell or plasma cell, by using recombinant DNA technology tools and methods, of an individual that was known to be infection with SARS-CoV-2 virus (See, abstract, entire article).
Zost et al 2020 teaches potent neutralizing mAbs recognizing non-overlapping sites, COV2-2196 and COV2-2130 (RBD binding or ACE2 blocking), bound simultaneously to Spike protein and synergistically neutralized authentic SARS-CoV-2 virus. A large panel of SARS-CoV-2 Spike protein-reactive mAbs from the B cells of two convalescing individuals who had been infected with SARS-CoV-2 in Wuhan China. The antibodies were isolated using diverse tools for isolation and cloning of single antigen-specific B cells and the antibody variable genes encoding monoclonal antibodies. The Mabs were potently neutralizing and protective human antibodies against SARS-CoV-2. The Mabs were specific for RBD, S2 and ACE2 blocking neutralizing function (See, abstract, Figure 1-2, section on Antibodies, entire article).
Liu et al 2020 teaches potent neutralizing monoclonal antibodies (recombinantly obtained using recombinant DNA technology and methods) against multiple epitopes on SARS-CoV-2 spike protein. Isolation of sixty-one SARS-CoV-2-neutralizing monoclonal antibodies from B cells of five patients infected with SARS-CoV-2 and admitted to hospital with severe coronavirus disease 2019 (COVID-19). Among these are nineteen antibodies that potently neutralized authentic SARS-CoV-2 in vitro, nine of which exhibited very high potency, with 50% virus-inhibitory concentrations of 0.7 to 9 ng ml−1. Epitope mapping showed that this collection of nineteen antibodies was about equally divided between those directed against the receptor-binding domain (RBD) and those directed against the N-terminal domain (NTD), indicating that both of these regions at the top of the viral spike are immunogenic. In addition, two other powerful neutralizing antibodies recognized quaternary epitopes that overlap with the domains at the top of the spike. Cryo-electron microscopy reconstructions of one antibody that targets the RBD, a second that targets the NTD, and a third that bridges two separate RBDs showed that the antibodies recognize the closed, ‘all RBD-down’ conformation of the spike. Several of these monoclonal antibodies are promising candidates for clinical development as potential therapeutic and/or prophylactic agents against SARS-CoV-2 (See, abstract, Fig 1-4, page 451 col 1 section on Isolation and construction of mAbs).
Tortorici et al 2020 teaches neutralization of SARS-CoV-2 by isolated monoclonal antibody S2E12 and S2M11 IgG or Fab by binding to RBD of spike protein. Peripheral blood samples were obtained from two donors who have recovered from SARS-CoV-2 infection. Samples were collected 46 and 61 days after symptoms onset, respectively. (See, Fig. 1, methods, entire article).
Thus, the claim 1 (and dependent claims 2-5 and 12-16) are rejected under 35 U.S.C. 101 as the claimed monoclonal antibody is a product of nature without modification of the sequence and the claims are directed to a genus of an antibody, monoclonal antibody that encompass entire B cell repertoire of VH and VL chain sequence comprising monoclonal antibodies from a SARS-CoV-2 infected individual’s B cell or plasma cells as recited supra, and because the claim does not include any additional features that could add significantly more to the exception.
Examiner’s suggestion: To overcome the 35 U.S.C. 101 rejection, the applicant may amend preamble of claim 1 as: An antibody comprising (delete “or”) antigen binding fragment thereof ……….
The dependent claims and withdrawn claims may be amended accordingly to be consistent with claim 1 scope.
Allowable Subject Matter
18. Claim 1: Elected species of antibody BG10-19: The SEQ ID NO: 276 of VH of BG10-19, SEQ ID NO: 368 of VH of BG10-19 and SEQ ID NO: 92, CDR3 of BG10-19 are free of prior art.
The dependent claims 2-5, 12-16 and 25-28 inherit the limitations of sequences for the elected antibody species BG10-19: the SEQ ID NO: 276, VH of BG10-19, SEQ ID NO: 368, VH of BG10-19 and SEQ ID NO: 92, CDR3 of BG10-19.
However, the claims 1-5, 12-16 and 25-28 are also rejected for improper Markush grouping of antibodies and applicant is required to address the rejections. The search was not expanded or considered to encompass the unelected improper Markush group of species.
19. Relevant Prior Art:
Xu et al 2000. Diversity in the CDR3 Region of VH Is Sufficient for Most Antibody Specificities. Immunity, Volume 13, Issue 1, 2000, Pages 37-45.
Conclusion
20. No claim is allowed.
21. Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAMADHAN J JADHAO whose telephone number is (703)756-1223. The examiner can normally be reached M-F 8:00-5:00.
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/SAMADHAN JAISING JADHAO/ Examiner, Art Unit 1672
/THOMAS J. VISONE/ Supervisory Patent Examiner, Art Unit 1672
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