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 without traverse of Group I claims 1-12 in the reply filed on 05/11/2026 is acknowledged.
Election of Species: Applicant elected species based on the CDR sequences disclosed for SKAI-DS84 are identified as:
light chain CDR1: SEQ ID NO: 17;
light chain CDR2: SEQ ID NO: 26;
light chain CDR3: SEQ ID NO: 38;
heavy chain CDR1: SEQ ID NO: 46;
heavy chain CDR2: SEQ ID NO: 61; and
heavy chain CDR3: SEQ ID NO: 77.
For compact prosecution, search was extended and considered to examine unelected species of the Markush group and other claims.
Status of Claims
3. Claims 1-19 filed on 01/28/2026 are pending.
4. Claims 13-19 (non-elected Groups II-IV) are withdrawn from examination.
5. Claims 1-12 are under examination.
Priority
6. This is a 371 National Stage of International Application No. PCT/KR2022/014794 filed
September 30, 2022, claiming priority based on Patent Application No. 10-2022-0085495 filed July 12, 2022 in Republic of Korea.
Information Disclosure Statement
7. The information disclosure statement (IDS) submitted on 06/22/2023 and 05/22/2025 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
8. Claims 1-12 are objected to because of the following informalities:
The applicant did not mark the non-elected claims 13-19 as withdrawn or cancelled when the response was filed for Restriction/Election on 05/11/2026.
Appropriate correction is required.
Claim Rejections - 35 USC § 112
9. 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 1-12 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.
The instant claim 1 has claimed a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8. The critical core structure (a single species with a specific (not variable) amino acid sequence) of CDRs is not recited in the claims or in the specification based on which the General Formulae 1-8 for CDRs are formulated to introduce variation of amino acids. The critical structure of CDRs on which the variability depends is not commensurate with the genus that comprise many envisioned species by the ordinary skills and therefore the meets and bound of claim not clear in light of specification, because a reliable point of reference sequence where the variability depends on is not recited in the claim or specification.
Claim Rejections - 35 USC § 112 (Written Description)
10. 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.
The claims 1-12 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 instant specification, the claimed neutralizing antibody includes a polyclonal antibody and a monoclonal antibody (see, page 6), a camel antibody (See, page 8).
The claims 1-12 are drawn to compositions comprising a genus of antibody and therefore the scope of claim 1 is generic (very broad). The claim 1 recites limitations that are generic, and the specification does not have support commensurate with the full scope of the claimed invention, “a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof”.
The claim 1 also recites alternate limitations an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8 that has many alternative substitutions represented by variant amino acid notations. The variant amino acid substitutions introducing thousands of species of “a claimed neutralizing antibody”.
The General Formulae 1-8 for light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 do not provide a “critical core structure of CDRs” claimed by using general formulae. The critical structure (demined a single specific amino acid sequence for CDR) on which the variability of the general formulae depends on are not provided in the specification or the claim 1 and dependent claims 2-12.
The following quotation from section 2163 of the Manual of Patent Examination
Procedure is a brief discussion of what is required in a specification to satisfy the 35 U.S.C. 112 written description requirement for a generic claim covering several distinct inventions:
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 applicant was in possession of the claimed genus... See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. '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.
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. The claim 1 has a functional limitation “A neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8. The resulting in “variant” antibody or fragments or fragments thereof encompassed by the instant claims 1-12 may or may not be effective in achieving the neutralizing efficacy or binding affinities similar to the antibodies that are derived from wild type and recombinant amino acid sequences (without mutations/substitution/variations).
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 genus of antibody (claim 1) with variant CDR species based on General Formulae 1-8 that is required to be satisfied through sufficient description of a representative number of species by actual reduction to practice showing similar neutralizing activity/efficacy of a SARS-CoV-2 coronavirus and variants thereof. Thousands different variants of antibody or the antigen binding fragment thereof are possible and can be envisioned by the ordinary skills given variability of the General Formulae 1-8 in claim 1 for the CDRs.
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 claims 1-12 since there is no or insufficient representative species and/or identifying characteristics to place applicant in possession of the generic scope of the claimed invention directed to a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8 for CDRs.
Claim Rejections - 35 USC § 112 (Scope of Enablement)
11. 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 1-12 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 claims 11-12, does not reasonably provide enablement for claims 1-10. 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 general formulae 1-8 for CDRs (claim 1 and claims 4-10).
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: Claims 1 and 4-10. The instant claim 1 has claimed a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8 without providing a definite point of a CDR sequence comprising a specific amino acid reference sequence for CDRs (in absence of critical core CDR structure) on which the variation of CDRs amino acids are dependent.
State of the prior art: At the time the invention no prior art is available to teach to produce engineered a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDRs1-3 and heavy chain CDRs1-3 is represented by an amino acid sequence of General Formulae 1-8 without providing a definite point of a CDR sequence comprising a specific amino acid reference sequence for CDRs (in absence of critical core CDR structure) on which the variation of CDRs amino acids are dependent. The functional limitation “neutralizing” is not reasonably possible to achieve at a desired higher efficacy of neutralization of SARS-CoV-2 virus or variant virus thereof for the claimed antibodies comprising CDR sequences of General Formulae 1-8 in claim 1 that has a very high level of variability and thousands of possible envisioned species generated due to variability in the General Formulae 1-8. See, 35 USC 112(b) and 112(a) written description rejection above.
Nature of the invention. The claims 1-12 are directed to a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDRs1-3 and heavy chain CDRs1-3 is represented by an amino acid sequence of General Formulae 1-8 without providing a definite point of a CDR sequence comprising a specific amino acid reference sequence for CDRs (in absence of critical core CDR structure) on which the variation of CDRs amino acids are dependent. The claim recites a functional limitation of neutralizing to the claimed variant antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof.
Working Examples. Reduction to practice is not achieved as the specification does not disclose even a single working example of a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof based on an antigen-binding fragment thereof comprising light chain CDRs1-3 and heavy chain CDRs1-3 that are not represented by CDRs comprising a specific species of variant amino acid sequence CDR species derived from General Formulae 1-8 on which the variation of CDRs amino acids is dependent.
The claim assigned a functional limitation of neutralizing to the claimed variant antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof but did not provide the working example(s) reduced to practice showing possession of “how to make and use” for claims 1 and 4-10.
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 CDRs based on General Formulae 1-8 to arrive at the inventions of broad generic claims 1 and 4-10 that comprise an antibody with a function of neutralization of SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof. It would require undue experimentation to cover the breadth of the claims that requires to achieve the function of neutralization to enable the full scope of the claims 1 and 4-10 for the claimed neutralizing activity to be reasonably effective for intended therapeutic applications in the SARS-CoV-2 virus infected subjects. The ordinary skills in the art would be burdened with planning, engineering the claimed CDRs, 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 CDRs based on General Formulae 1-8 to arrive at the inventions of broad generic claims 1 and 4-10 that comprise an antibody with a function of neutralization of SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof 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 and 4-10 and scarcity of guidance in the specification, and the unpredictable nature of the art. The enablement inquiry for claims that include functional requirements “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 and 4-10 is highly unpredictable to reduce to the practice.
Breadth of claims. The claims 1-12 are directed to a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof based on an antigen-binding fragment thereof comprising light chain CDRs1-3 and heavy chain CDRs1-3 that are not represented by CDRs comprising a specific species of variant amino acid sequence derived from General Formulae 1-8 on which the variation of CDRs amino acids is dependent. The claim assigned a functional limitation of neutralizing to the claimed variant antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof but did not provide the working example(s) reduced to practice showing possession of “how to make and use” for claims 1 and 4-10. 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 general formulae 1-8 for CDRs (claim 1 and claims 4-10).
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 neutralize SARS-CoV-2 virus and variant viruses) 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.
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)”.
The amount of direction provided by the inventor: The specification does not provide guidance regarding “how to make and use” of the claimed composition of claims 1 and 4-10 by reduction to practice by working example in the specification showing enablement for claims 1 and 4-10 showing achievement of a claimed function of a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof based on an antigen-binding fragment thereof comprising light chain CDRs1-3 and heavy chain CDRs1-3 that are not represented by CDRs comprising a specific species of variant amino acid sequence CDR species derived from General Formulae 1-8 on which the variation of CDRs amino acids is dependent. The claim assigned a functional limitation of neutralizing to the claimed variant antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof but did not provide the working example(s) reduced to practice showing possession of “how to make and use” for claims 1 and 4-10.
Given the breadth of the claims 1 and 4-10, 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 1-12 and therefore consequently raise doubt as to the enablement of full scope of the claims.
Claim Rejections - 35 USC § 112 (Improper Markush Grouping)
12. Improper Markush Grouping Rejection.
The claims 1-12 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 claim 1, the Markush grouping of a claimed antibody CDRs represented by General Formulae 1-8 is 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:
In the instant case, the claim 1 recites a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8. The critical core structure (a single species with a specific (not variable) amino acid sequence) of CDRs is not recited in the claims or in the specification based on which the General Formulae 1-8 for CDRs are formulated to introduce variation of amino acids. The critical structure of CDRs on which the variability depends is not commensurate with the genus that comprise thousands of envisioned species by the ordinary skills as there is not a reliable point of reference sequence where the variability depends on is not recited in the claim or specification. Additionally, claims 4-10 recite additional improper Markush groups of antibodies or CDRs.
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 reference sequence for the structure of the CDRs on which the variability of the general formulae depends 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.
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.
This is a rejection on the merits and may be appealed to the Board of Patent Appeals and Interferences in accordance with 35 U.S.C. §134 and 37 CFR 41.31(a)(1).
Claim Interpretation
13. 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 instant claim 1 has claimed a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, or an antigen-binding fragment thereof, wherein the antibody or an antigen-binding fragment thereof comprises light chain CDR1, CDR2 and CDR3 and heavy chain CDR1, CDR2 and CDR3, and the light chain CDR1 is represented by an amino acid sequence of General Formulae 1-8.
The claim 1 is interpreted to encompass thousands of possible species of variant antibodies based on variant CDRs and possible combinations of different VH and VL CDRs.
According to the instant specification, the claimed neutralizing antibody includes a polyclonal antibody and a monoclonal antibody (see, page 6), a camel antibody (See, page 8).
Claim Rejections - 35 USC § 101
14. 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 1-12 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 claims2-12) are interpreted to be directed to a product of nature, a neutralizing antibody against SARS-coronavirus 2 (SARS-CoV2) or a variant virus thereof, that is naturally derived as an antibody or recombinantly derived from a single memory B cell of obtained from a SARS CoV-2 survivor 48 days following symptom onset in an individual. A antibody is also interpreted to comprise wild type HV and VL sequence without amino acid substitution to generate a recombinant monoclonal antibody. An antibody in a broadest sense is interpreted as a polyclonal antibody that comprise many monoclonal antibodies that neutralize SARS-CoV-2 virus or the variant viruses.
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 2-16, and 24) are directed to a statutory category, e.g. composition of matter (the claimed antibody with a function of neutralizing a SARS-CoV-2 virus and variant viruses, therefore, statutory category eligibility, Step 1: Yes.
Step 2: As described in the instant specification and the prior art Corti et al 2021 (US20210261650A1, 08/26/2021, recited in IDS filed on 06/22/2023), and further in view of Cameroni et al 2022 (Nature, 602(7898), 664-670, published online: 23 December 2021, recited in IDS filed on 06/22/2023) as recited below the claimed genus of 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 antibody which naturally comprise the antigen binding fragment, Fc, VH and VL chains. The antibody has a function of neutralizing a SARS-CoV-2 virus. The claimed antibodieshas 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 2-12) fails to integrate (e.g. composition of matter-the claimed neutralizing antibody with a function of neutralizing a SARS-CoV-2 virus 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 2-12) does/do not include additional elements that are sufficient to amount to significantly more to the claimed composition of matter a monoclonal antibody (a genus) (than the judicial exception because the claims recite a antibody and additional antibody species in the genus, as to constitute an “inventive concept” (e.g. improvement) Step 2B: No.
Corti et al 2021 is in the art and disclosed antibodies and antigen-binding fragments thereof that can bind to a SARS-CoV-2 antigen and are capable of neutralizing a SARS-CoV-2 infection. Also provided are polynucleotides that encode an antibody or antigen-binding fragment, vectors and host cells that comprise a polynucleotide, pharmaceutical compositions, and methods of use to treat or diagnose a SARS-CoV-2 infection (See, abstract). Corti et al 2021 teaches SARS-CoV-2 neutralization of infection by neutralization by donor plasma from SARS-CoV-1 survivors (See, para [0005]-[007], Examples 1-4, entire prior art). The plasma or B cell derived antibodies of Corti et al 2021 capable of neutralizing a SARS-CoV-2 virus would reasonably be expected to comprise diverse antibody CDR amino acid sequences to render obvious the generic variable CDR amino acid sequences as claimed in instant claim 1.
Cameroni et al 2022 teaches broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Cameroni et al 2022 disclosed neutralization of Omicron SARS-CoV-2 VSV pseudovirus (equivalent to SARS-CoV-2 Omicron strain for the function of antibody neutralization) by plasma derived from convalescent and vaccinated individuals and thus teaches the polyclonal antibodies in regard to the BRI of the claim 1 (See, page 666, Fig. 2 and legends). The plasma derived antibodies of Cameroni et al 2022 capable of neutralizing a SARS-CoV-2 virus would reasonably be expected to comprise diverse CDR amino acid sequences to render obvious the generic variable antibody CDR amino acid sequences as claimed in instant claim 1. Cameroni et al 2022 disclosed 3 monoclonal antibodies retaining unaltered neutralization potency including the ACE2-mimicking S2K146 antibody (See, abstract, Fig 2-3 and associated legends).
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 (antibodies) 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 2-12) are rejected under 35 U.S.C. 101 as the claimed antibody is a product of nature without modification of the sequence and the claims are directed to a genus of 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.
Claim Rejections - 35 USC § 103
15. 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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
16. Claims 1-3 are rejected under 35 U.S.C. 103 as being unpatentable over Corti et al 2021 (US20210261650A1, 08/26/2021, recited in IDS filed on 06/22/2023), and further in view of Cameroni et al 2022 (Nature, 602(7898), 664-670, published online: 23 December 2021, recited in IDS filed on 06/22/2023).
Claims 1-3: In view of the specification, and the broadest reasonable interpretation (BRI), the instant claim 1 is interpreted to comprise a polyclonal antibody, or a monoclonal antibody or a recombinant antibody that specifically neutralize a SARS-CoV-2 virus and the variant virus thereof (See, instant specification, page numbers 6-8).
Corti et al 2021 is in the art and disclosed antibodies and antigen-binding fragments thereof that can bind to a SARS-CoV-2 antigen and are capable of neutralizing a SARS-CoV-2 infection. Also provided are polynucleotides that encode an antibody or antigen-binding fragment, vectors and host cells that comprise a polynucleotide, pharmaceutical compositions, and methods of use to treat or diagnose a SARS-CoV-2 infection (See, abstract). Corti et al 2021 teaches SARS-CoV-2 neutralization of infection by neutralization by donor plasma from SARS-CoV-1 survivors (See, para [0005]-[007], Examples 1-4, entire prior art). The plasma or B cell derived antibodies of Corti et al 2021 capable of neutralizing a SARS-CoV-2 virus would reasonably be expected to comprise diverse antibody CDR amino acid sequences to render obvious the generic variable CDR amino acid sequences as claimed in instant claim 1.
Cameroni et al 2022 teaches broadly neutralizing antibodies overcome SARS-CoV-2 Omicron antigenic shift. Cameroni et al 2022 disclosed neutralization of Omicron SARS-CoV-2 VSV pseudovirus (equivalent to SARS-CoV-2 Omicron strain for the function of antibody neutralization) by plasma derived from convalescent and vaccinated individuals and thus teaches the polyclonal antibodies in regard to the BRI of the claim 1 (See, page 666, Fig. 2 and legends). The plasma derived antibodies of Cameroni et al 2022 capable of neutralizing a SARS-CoV-2 virus would reasonably be expected to comprise diverse CDR amino acid sequences to render obvious the generic variable antibody CDR amino acid sequences as claimed in instant claim 1. Cameroni et al 2022 disclosed 3 monoclonal antibodies retaining unaltered neutralization potency including the ACE2-mimicking S2K146 antibody (See, abstract, Fig 2-3 and associated legends).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the prior art teaching of Corti et al 2021 with additional teachings of Cameroni et al 2022 on Omicron variant SARS-CoV-2 neutralizing antibodies with a motivation to develop broadly neutralizing antibodies or antigen binding fragments thereof for passive therapy or diagnostics to arrive at the invention of claim 1. There would have been a reasonable expectation of success given the applied prior arts and required research reagents and laboratory skills available with one of the ordinary skills in the art. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 1. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
17. Claim 12 is rejected under 35 U.S.C. 103 as being unpatentable over combined prior art teachings of Corti et al 2021 (US20210261650A1, 08/26/2021, recited in IDS filed on 06/22/2023), and Cameroni et al 2022 (Nature, 602(7898), 664-670, published online: 23 December 2021, recited in IDS filed on 06/22/2023) further in view of Lee et al 2016 (2016-12-06 Publication of US9512220B2), Nussenzweig et al 2022 (WO2022155324A1, 07/21/2022, with earlier priority to US 63/199676 filed 01/15/2021), Nam et al 2020 (US10604571B2, 03/31/2020), and Westendorf et al 2022 (US11370828B2, 06/28/2022).
The combined prior art teachings of Corti et al 2021 (US20210261650A1), and Cameroni et al 2022 teaches genus of a neutralizing antibody of claim 1 that inherently comprise VH and VL CDRs, however do not teach the added limitation of instant claim 12 wherein the antibody or an antigen-binding fragment thereof comprises light chain FR1-FR4 and heavy chain FR1-FR4, represented by an amino acid sequence of SEQ ID NOs 1-8, respectively.
Lee et al 2016 (2016-12-06 Publication of US9512220B2) disclosed non-SARS-CoV-2 antibody with SEQ ID NO: 50 that has 100% identity to the instant claimed SEQ ID NOs: 1-4.
Qy 1 QSVLTQPPSASGTPGRRVTISC-------------WYQQLPGTAPKLLIY----RPSGVP 43
|||||||||||||||||||||| ||||||||||||||| ||||||
Db 1 QSVLTQPPSASGTPGRRVTISCSGSSPNIGNNTVNWYQQLPGTAPKLLIYSDSHRPSGVP 60
Qy 44 DRFSGSKSGTSASLAISGLRSEDEADYYC---------YVFGGGTKLTVL 84
||||||||||||||||||||||||||||| ||||||||||||
Db 61 DRFSGSKSGTSASLAISGLRSEDEADYYCGAWDYSLNAYVFGGGTKLTVL 110
Nussenzweig et al 2022 (WO2022155324A1, 07/21/2022, with earlier priority to US 63/199676 filed 01/15/2021) disclosed neutralizing anti-SARS-CoV-2 antibodies or antigen- binding fragments thereof with a SEQ ID NO: 1844 that has 100% identity due to 2 conservative amino acid substitutions with instant claimed SEQ ID NOs: 1-4.
Matches 82; Conservative 2; Mismatches 0; Indels 26; Gaps 3;
Qy 1 QSVLTQPPSASGTPGRRVTIS-------------CWYQQLPGTAPKLLIY----RPSGVP 43
|||||||||||||||:||||| |||||||||||||||| ||||||
Db 1 QSVLTQPPSASGTPGQRVTISCSGSSSNIGSNYVCWYQQLPGTAPKLLIYRNNLRPSGVP 60
Qy 44 DRFSGSKSGTSASLAISGLRSEDEADYYC---------YVFGGGTKLTVL 84
||||||||||||||||||||||||||||| :|||||||||||
Db 61 DRFSGSKSGTSASLAISGLRSEDEADYYCAAWDDSLSVWVFGGGTKLTVL 110
Nam et al 2020 (US10604571B2, 03/31/2020) disclosed non-SARS-CoV-2 antibody with SEQ ID NO: 23 that has 100% identity to the instant claimed SEQ ID NOs: 5-8.
Matches 92; Conservative 0; Mismatches 0; Indels 22; Gaps 3;
Qy 1 EVQLLESGGGLVQTGGSLRLSCAASGFTF-----SWVRQAPGKGLEWVS---------YY 46
||||||||||||||||||||||||||||| ||||||||||||||| ||
Db 1 EVQLLESGGGLVQTGGSLRLSCAASGFTFSDYAMSWVRQAPGKGLEWVSWIYYDSGSKYY 60
Qy 47 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA--------WGQGTLVTV 92
||||||||||||||||||||||||||||||||||||| |||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCAKLNGDFDYWGQGTLVTV 114
Westendorf et al 2022 (US11370828B2, 06/28/2022) teaches neutralizing antibodies against SARS-CoV-2 and disclosed SEQ ID NO: 753 that has 100% identity to the instant claimed SEQ ID NOs: 5-8.
Matches 91; Conservative 0; Mismatches 1; Indels 21; Gaps 3;
Qy 1 EVQLLESGGGLVQTGGSLRLSCAASGFTF-----SWVRQAPGKGLEWVS---------YY 46
||||||||||||| ||||||||||||||| ||||||||||||||| ||
Db 1 EVQLLESGGGLVQPGGSLRLSCAASGFTFSTYAMSWVRQAPGKGLEWVSAISGSGGSTYY 60
Qy 47 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCA-------WGQGTLVTV 92
||||||||||||||||||||||||||||||||||||| |||||||||
Db 61 ADSVKGRFTISRDNSKNTLYLQMNSLRAEDTAVYYCASGYSPDYWGQGTLVTV 113
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined prior art teaching of Corti et al 2021 and Cameroni et al 2022 on Omicron variant SARS-CoV-2 neutralizing antibodies with additional teachings of Lee et al 2016, Nussenzweig et al 2022, Nam et al 2020 and Westendorf et al 2022 on the sequence of the claimed FR1-8 of SEQ ID NOs: 1-8 to arrive at the invention of claim 12
with a motivation to develop a neutralizing antibody or antigen binding fragments thereof for therapeutic application in SARS-CoV-2 virus or variant infected subject and for commercial success. There would have been a reasonable expectation of success given the applied prior arts teachings and the genus of an antibody (comprising an entire repertoire of VH and VL CDRs) neutralizing SARS-CoV-2 and variants rendered obvious by Corti et al 2021 and Cameroni et al 2022 and required research reagents and laboratory skills available with one of the ordinary skills in the art. Thus, the invention as a whole was clearly prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention. This is analogous to some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the invention as claimed in claim 12. See KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) (see MPEP § 2143, example of rationales, A-G).
Allowable Subject Matter
18. Claim 11: The claim is objected to as being based on a rejected base claim, however the specific sequences of VH and VL chain CDRs claimed for antibody species recited in limitations (1) – (16) are free of prior art. The prior arts do not teach 100% identity to the claimed amino acid sequences in the SEQ ID NOs.
19. Relevant Prior Arts for claim 1 generic formulae CDRs
Nussenzweig et al 2021 (US20210332110A1, 10/28/2021). Neutralizing anti-SARS-CoV-2 antibodies and methods of use thereof. Disclosure is related to instant claimed SEQ ID NO: 80 (claim 1).
DeFalco et al 2020 (US20200325242A1, 10/15/2020). Antibodies that bind tumor tissue for diagnosis and therapy. Disclosure is related to the concept of Generic Formule for antibody CDrs to instant claim 1 (see, description of the prior art). Disclosure is related to instant claimed SEQ ID NO: 80 (claim 1).
Nussenzweig et al 2022 (WO2022155324A1, 07/21/2022, with earlier priority to US 63/199676 filed 01/15/2021) disclosed neutralizing anti-SARS-CoV-2 antibodies or antigen- binding fragments thereof with a SEQ ID NO: 1321 and 5523. Disclosure is related to instant claimed SEQ ID NO: 80 and 83 (claim 1).
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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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas J Visone can be reached at 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAMADHAN JAISING JADHAO/Examiner, Art Unit 1672
/BENNETT M CELSA/Primary Examiner, Art Unit 1600
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