DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Examiner’s Note
Examination of the instant application has been transferred to Examiner Jeff Sifford of Art Unit 1671. Examiner Sifford may be contacted at 571-272-7289 or jeffrey.sifford@uspto.gov.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-9, 13, and 15, and the required species: antibody 88, comprising a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 having amino acid sequences set forth in SEQ ID NOs: 105-110, respectively, in the reply filed on 3/30/2026 is acknowledged.
Claims 6, 10, 14, 18, 20, 22, and 26 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention or species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 3/30/2026.
Claims 1-5, 7-9, 13, and 15 are under examination on the merits
Information Disclosure Statement
The Information Disclosure Statements (IDSs) submitted on 12/20/2023 and 3/30/2026 are in compliance with 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 CFR 1.831(c). Sequence identifiers for sequences (i.e., “SEQ ID NO:X” or the like) must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Amended drawings in accordance with 37 CFR 1.121(d) inserting the required sequence identifiers;
AND/OR
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required sequence identifiers (i.e., “SEQ ID NO:X” or the like) into the Brief Description of the Drawings, consisting of:
• A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
• A copy of the amended specification without markings (clean version); and
• A statement that the substitute specification contains no new matter.
Drawings
The drawings are objected to because they contain amino acid sequences without the proper sequence identifiers from the sequence listing (Figs. 5C, 6A, 14A, and 36B). Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code on pp. 19, 122, 129, 131, and 144. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http://, www., or other browser-executable code. See MPEP § 608.01.
Claim Objections
Claim 8 is objected to because of the following informalities: it recites “a IgG1 constant region” on lines 1-2, but should instead recite “an IgG1 constant region.” Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Scope of Enablement
Claims 1-2, 4-5, 8-9, 13, and 15 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 an antibody capable of binding SARS-CoV-2 spike protein, wherein the antibody comprises a complete set of parental CDRs, does not reasonably provide enablement for similar antibodies containing an incomplete set of CDRs or any mutated CDRs that specifically bind to SARS-CoV-2 spike protein. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make or use the invention commensurate in scope with these claims.
The breadth of the claims is found in claim 1.
The nature of the invention is an antibody that bind the spike protein of SARS-CoV-2, wherein the antibody (a) comprises at least three CDRs of antibody 88 and/or (b) binds to the same epitope as or competes with antibody 159, 45, or 384 (claim 1). Claims 2, 4, 5, 8, 13, and 15 depend from claim 1 and thus have the same issue as claim 1. Claims 2 and 5 also recite antibodies that comprise a heavy chain variable domain and/or light chain variable domain that is at least 80% identical to the corresponding variable domains of antibody 88. Thus, claims 2 and 5 encompass antibodies comprising a heavy chain and light chain variable domain sequences having at least 80% identity to those of antibody 88, and does not require specific CDRs, and therefore encompasses antibodies wherein the variable domains to possess different CDRs that are mutant relative to antibody 88. Claim 4 recites antibodies comprising [..] (j) a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 having an amino acid sequence set forth in SEQ ID NOs: 105 to 110, respectively, the claim language “having an amino acid sequence of” is interpreted to mean that the claimed antibody may contain CDRs that are fragments of SEQ ID NOs: 105 to 110; it does not require the complete sequence of each of the claimed CDRs.
The level of skill of one skilled in this art is high.
The specification teaches a number of antibodies that bind to SARS-CoV-2 spike protein, and defines their 6 CDRs (CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3, and variable domains). See e.g., Table 1. These teachings do not enable the full breadth of the claims because an antibody lacking any of the 6 parental CDRs would not predictably bind antigen.
The state of the prior art is such that it is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). 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 immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30).
Additionally, Bendig M. M. (Methods: A Companion to Methods in Enzymology, 1995; 8:83-93) reviews that the general strategy for “humanizing” antibodies involves the substitution of all six CDRs from a rodent antibody that binds an antigen of interest, and that all six CDRs are involved in antigen binding (see entire document, but especially Figures 1-3). It is noted that Bendig used Kabat CDRs in their humanization process (Pg. 86, Column 2, Paragraph, second). Similarly, the skilled artisan recognized a “chimeric” antibody to be an antibody in which both the heavy chain variable region (which comprises the three heavy chain CDRs) and the light chain variable region (which comprises the three light chain CDRs) of a rodent antibody are recombined with constant region sequences from a human antibody of a desired isotype (see entire document, but especially Figures 1-3).
Thus, the state of the art recognized that it would be highly unpredictable that a specific antibody binding domain comprising less than all six parental CDRs would have antigen binding function. The minimal structure which the skilled artisan would consider predictive of the function of binding the antigen of an antibody includes six CDRs (three from the heavy chain variable region and three from the light chain variable region) in the context of framework sequences which maintain their correct spatial orientation and have the requisite binding function. One of skill in the art would neither expect nor predict the appropriate functioning of the antibodies as broadly as currently claimed.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by Paul and Bendig, the lack of guidance and direction provided by applicants, and the absence of working examples, undue experimentation would be required to make and use functional antibodies with binding domains having fewer than all six CDRs with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention.
In the case of antibodies, it is especially important to disclose which residues are permissive to mutation. 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 et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract).
Not knowing, absent further experimentation, which modifications function and which do not, when, as set forth above, even a single change of an encoded amino acid can unpredictably affect antibody structure and function, leads to one having no predictability or expectation of success for the function of any given antibody modification. Such random experimentation to identify at a later time what structure or fragment or modification is or is not functional and is embraced by Applicant’s claims is undue experimentation. This affects all claims that can mutate any CDR by reciting percent identity, for example claims 2, 4, and 5.
Moreover, claims not containing elements critical or essential to the practice of the invention, such as antibodies or antibody fragments not having all of the relevant functional complementarity determining regions (CDRs) in the proper site on an appropriate antibody heavy or light chain framework, are not enabled by the disclosure. See In re Mayhew, 527 F.2d 1229, 188 USPQ 356 (CCPA 1976).
Note that an enabling disclosure for the preparation and use of only a few analogs of a product does not enable all possible analogs where the characteristics of the analogs are unpredictable. See Amgen Inc. v. Chugai Pharmaceutical Co. Ltd. (18 USPQ 2d 1027 (CAFC 1991)).
Regarding claim 13, Applicant broadly claims one or more polynucleotides encoding the antibody according to claim 1, one or more vectors comprising said polynucleotides, or a host cell comprising said vectors. The claim reads on a cell within a transgenic animal or a transgene therein given that the term "isolated" is not denoted in describing the host cell, nucleic acid, or vector.
With respect to the unisolated host cells and transgenes as “nucleic acids” or “vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill could not predict the phenotype of transgenics. The art of transgenic animals has for many years stated that the unpredictability lies, in part, with the site or sites of transgene integration into the target genome and that "the position effect" as well as unidentified control elements are recognized to cause aberrant expression of a transgene (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
The elements of the particular construct used to make transgenic animals are also held to be critical, and they must be designed case by case without general rules to obtain good expression of a transgene; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 4065-4072). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo PHOSITA could make a host organism with functional transgene that encodes the instantly antibody, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by therapeutic antibodies such as the one instantly recited. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nature Reviews Drug Discovery, Vol. 9, Pg. 325-337, 2010) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, previously raised and new, transgenes are not enabled.
At the time of filing, the phenotype of a transgene and transgenic cell contained within any animal was unpredictable. The claims as written, encompassing a transgene and cell in a transgenic animal, is not adequately described in the specification as to prevent excessive experimentation by the public to generate and use the invention. Applicants can obviate the instant rejection by amending the claim to recite the term "isolated" before the recitation, "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. Applicant may consider using purified in such claims if description is appropriate for such a term and it is not redefined away from standard meaning. Method claims using these products should also carry the appropriate adjectives above.
In view of the lack of the predictability of the art to which the invention pertains as evidenced by the art above, the lack of guidance and direction provided by Applicant, and the absence of working examples, undue experimentation would be required to make and use functional polynucleotides that produce antibodies comprising fewer than all six parental CDRs or comprising mutated versions thereof, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed antibodies are functional, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claim is rejected here.
Enablement – Deposit
Claims 1-5, 7-9, 13 and 15 are rejected under 35 U.S.C. § 112 (pre-AIA ), first paragraph or 35 U.S.C. 112(a), because the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention, because the specification does not provide evidence that the claimed biological materials are (1) known and readily available to the public; (2) reproducible from the written description.
It is unclear if a cell line which produces an antibody having the exact chemical identity of antibody 88 is known and publicly available, or can be reproducibly isolated without undue experimentation. Therefore, a suitable deposit for patent purposes is suggested. Without a publicly available deposit of the above cell line, one of ordinary skill in the art could not be assured of the ability to practice the invention as claimed. Exact replication of: (1) the claimed cell line; (2) a cell line which produces the chemically and functionally distinct antibody claimed; and/or (3) the claimed antibody's amino acid or nucleic acid sequence is an unpredictable event.
Harris (Biotechnology, Vol. 11, Pg. 1293-1297, 1993) describes heterogeneity in the heavy chain of a recombinant antibody directed against human epidermal growth factor receptor-2 (Abstract). During transfection of antibody heavy and light chain genes into Chinese hamster ovary cells, the mutation Y376Q developed. When the cell line was propagated, 10% of subclones produced high levels of this variant while 90% produced antibody with the expected heavy and light chain sequences (Abstract). Therefore, alterations to antibody amino acid sequence do occur in processes of antibody reproduction without a hybridoma and can affect the reproducibility of a specific antibody species. Qin (US2022/0281997, published 09/08/2022) teaches that a monoclonal antibody is obtained from a population of substantially homogeneous antibodies wherein each is the same and/or binds the same epitope and also includes the antibody containing naturally occurring mutations that occurred during monoclonal antibody production (0069). Such variants are generally present in small amounts (0069). However, this makes clear that an antibody clone such antibody 88 need not contain only the VH and VL sequences provided by Applicant in the specification, but as a clone, can contain other sequences not provided. Thus, for practice of making and using the full scope of the claim, which reads on antibodies in an antibody 88 preparation with mutations in the CDRs and variable regions generally, deposit of the antibody is required.
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 et al (Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, March 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function. Colman P. M. (Research in Immunology, 145:33-36, 1994) teaches that even a very conservative substitution may abolish binding or may have very little effect on the binding affinity (see pg. 35, top of left column and pg. 33, right column). Taken together, it would require undue experimentation to reproduce the claimed antibody species antibody 88. Deposit of the hybridoma would satisfy the enablement requirements of 35 U.S.C. § 112, first paragraph. See, 37 C.F.R. 1.801-1.809.
If the deposit is made under the provisions of the Budapest Treaty, filing of an affidavit or declaration by applicant or assignees or a statement by an attorney of record who has authority and control over the conditions of deposit over his or her signature and registration number stating that the deposit has been accepted by an International Depository Authority under the provisions of the Budapest Treaty and that all restrictions upon public access to the deposited material will be irrevocably removed upon the grant of a patent on this application. This requirement is necessary when deposits are made under the provisions of the Budapest Treaty as the Treaty leaves this specific matter to the discretion of each State.
If the deposit is not made under the provisions of the Budapest Treaty, then in order to certify that the deposits comply with the criteria set forth in 37 CFR 1.801-1.809 regarding availability and permanency of deposits, assurance of compliance is required. Such assurance may be in the form of an affidavit or declaration by applicants or assignees or in the form of a statement by an attorney of record who has the authority and control over the conditions of deposit over his or her signature and registration number averring:
(a) during the pendency of this application, access to the deposits will be afforded to the Commissioner upon request:
(b) all restrictions upon the availability to the public of the deposited biological material will be irrevocably removed upon the granting of a patent on this application:
(c) the deposits will be maintained in a public depository for a period of at least thirty years from the date of deposit or for the enforceable life of the patent of or for a period of five years after the date of the most recent request for the furnishing of a sample of the deposited biological material, whichever is longest; and
(d) the deposits will be replaced if they should become nonviable or non-replicable.
In the instant case, the specification fails to state that a hybridoma that produces the antibody 88 was deposited. Further, it is not clear that a deposit was made under the terms of the Budapest Treaty, nor is there available a viability statement, i.e. one certifying that the deposit was viable at the time of the deposit or a certificate verifying such from the depository.
Amendment of the specification to recite the date of deposit and the complete name and address of the depository is required. As an additional means for completing the record, applicant may submit a copy of the contract with the depository for deposit and maintenance of each deposit.
If a deposit is made after the effective filing date of the application for patent in the United States, a verified statement is required from a person in a position to corroborate that the biological material described in the specification as filed is the same as that deposited in the depository, stating that the deposited material is identical to the biological material described in the specification and was in the applicant's possession at the time the application was filed.
Applicant's attention is directed to In re Lundak, 773 F.2d. 1216, 227 USPQ 90 (CAFC 1985) and 37 CFR 1.801-1.809 for further information concerning deposit practice.
Written Description
Claims 1-2, 4-5, 8-9, 13, and 15 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.
The instant claims above are drawn to a genus of antibodies capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody (a) comprises at least three CDRs of antibody 88 or (b) binds to the same epitope as or competes with antibody 159, 45, or 384 (claim 1). They are not defined by any structure other than comprising at least three CDRs of antibody 88. However, antibodies generally require at least 6 CDRs to function, yet only three CDRs are required for part (a), and no CDRs are required for part (b). When one goes to the instant specification to identify a representative number of species to define the claimed genera with respect to such an antibody, they do not find any representative species of an antibody able to bind spike protein of coronavirus SARS-CoV-2 with only three or zero CDRs. Similarly, claim 2 encompasses an antibody comprising (a) at least four or five CDRs of antibody 88, so there is insufficient structure described for the claimed antibodies. Claim 2 also recites an antibody comprising (b) a heavy chain variable domain, (c) a light chain variable domain, or (d) a heavy chain variable domain and a light chain variable domain having at least 80% identity to respective heavy chain variable domain and/or light chain variable domain of antibody 88. Notably, claim 2 does not require specific CDRs, and allows for the variable domains to possess different CDRs that are mutant relative to antibody 88. Regarding claim 4, which recites (j) a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 having an amino acid sequence set forth in SEQ ID NOs: 105 to 110, respectively, the claim language “having an amino acid sequence” is interpreted to mean that the claimed antibody may contain CDRs that are fragments of SEQ ID NOs: 105 to 110; it does not require the complete sequence of each of the claimed CDRs. Claim 5 also fails to meet the written description requirement, because it encompasses an antibody comprising a heavy chain and light chain variable domain sequences having at least 80% identity to those of antibody 88, and does not require specific CDRs, and therefore encompasses antibodies wherein the variable domains to possess different CDRs that are mutant relative to antibody 88.
Even if the prior art is aware of such antibodies, the totality of known antibodies would not be representative of each entire genus for the reasons discussed below. Claims 2, 4-5, 8-9, 13, and 15 depend from claim 1 but fail to resolve this lack of defined structure (CDRs).
On 22 February 2018, the USPTO provided a Memorandum clarifying the Written Description Guidelines for claims drawn to antibodies. That Memorandum indicates that, in compliance with recent legal decisions, the disclosure of a fully characterized antigen no longer is sufficient written description of an antibody to that antigen. Accordingly, the instant claims have been evaluated in view of that guidance.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
An applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613.
Furthermore, to satisfy the written description requirement for the genus antibody capable of binding to SARS-CoV-2 spike protein with incompletely defined CDRs, Applicant must adequately describe representative antibodies to reflect the structural diversity of the claimed genus. See Eli Lilly, 119 F.3d at 1568 (“[N]aming a type of material generally known to exist, in the absence of knowledge as to what that material consists of, is not a description of that material.”); Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993) (“Claiming all DNA[s] that achieve a result without defining what means will do so is not in compliance with the description requirement; it is an attempt to preempt the future before it has arrived.”).
MPEP § 2163 states that the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or 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. A “representative number of species” means that the species which are adequately described are representative of the entire genus. See, e.g., AbbVie Deutschland GMBH v. Janssen Biotech, 759 F.3d 1285, 111 USPQ2d 1780 (Fed. Cir. 2014). Thus, when there is substantial variation within the genus, as here in which the antibodies claimed can have incomplete CDR sets, one must describe a sufficient variety of species to reflect the variation within the genus. The disclosure of only one species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure “indicates that the patentee has invented species sufficient to constitute the gen[us].” See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 1615. “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” One of skill in this art cannot envision the structure of any antibody comprising zero, three, four, or five CDRs that alone specifically binds to a SARS-CoV-2 spike protein. Therefore, since no species is provided to represent these genera, the claims encompassing the same clearly fail the written description requirement.
Functionally defined genus claims can be inherently vulnerable to invalidity challenge for lack of written description support, especially in technology fields that are highly unpredictable, where it is difficult to establish a correlation between structure and function for the whole genus or to predict what would be covered by the functionally claimed genus. See ABBVIE DEUTSCHLAND GMBH & 2 CO. v. JANSSEN BIOTECH, INC., Appeals from the United States District Court for the District of Massachusetts in Nos. 09-CV-11340-FDS, 10-CV-40003-FDS, and 10-CV-40004-FDS, Judge F. Dennis Saylor, IV. See also Ariad, 598 F.3d at 1351 (“[T]he level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology.”); see also Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1352 (Fed. Cir. 2011) (noting the technical challenges in developing fully human antibodies of a known human protein).
For a claim to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011).
“Functional” terminology may be used “when the art has established a correlation between structure and function” but “merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing one has invented a genus and not just a species.” Ariad Pharmaceuticals Inc. v. Eli Lilly & Co., 598 F3d 1336, 94 USPQ2d 1161, 1171 (Fed Cir. 2010). Since the CDR set of each antibody is responsible for antigen binding function of an antibody, and said set varies structurally from antibody to antibody, there is no correlation between structure and function between the members of an antibody genus. One cannot “represent” the entire genus defined only by function with any structural consensus. Thus, functional language should not be used to define an antibody genus. Rather, structure should be used.
Even when several species are disclosed, these are not necessarily representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (“The ’128 and ’485 patents, however, only describe species of structurally similar antibodies that were derived from Joe-9. Although the number of the described species appears high quantitatively, the described species are all of the similar type and do not qualitatively represent other types of antibodies encompassed by the genus.”). Thus, when there is substantial variation within the genus, as here, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. Since each genus recited in the instant claims is large, it would be very challenging to describe sufficient species to cover the structures of the entire genus. Four species is certainly not adequate.
Overall, at the time the invention was made, the level of skill for preparing antibodies and then selecting those antibodies with desired functional properties was high. However, even if a selection procedure was, at the time of the invention, sufficient to enable the skilled artisan to identify antibodies with the recited functional properties, the written description provision of 35 U.S.C § 112 is severable from its enablement provision. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336 (Fed. Cir. 2010); see also Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1876 (Fed. Cir. 2011) (“The fact that a fully-human antibody could be made does not suffice to show that the inventors of the '775 patent possessed such an antibody.”) Absent the conserved structure provided by all six CDRs of a parental antibody in the context of appropriate VH and VL framework sequences, the skilled artisan generally would not be able to visualize or otherwise predict, a priori, what an antibody with a particular set of functional properties would look like structurally.
Since no antibodies possessing merely three, four, or five CDRs are shown to be capable of binding to SARS-CoV-2 spike protein, the instant claims above clearly fail the written description requirement. A representative number of species has not been taught to describe these genera. Given the well-known high level of polymorphism of immunoglobulins / antibodies, the skilled artisan would not have been in possession of the vast repertoire of antibodies and the unlimited number of antibodies encompassed by the claimed invention; one of skill in the art would conclude that applicant was not in possession of the structural attributes of a representative number of species possessed by the members of the genera of antibodies capable of binding SARS-CoV-2 spike protein that only comprise three, four, or five CDRs, partial CDRs, or heavy chain variable domains or light chain variable domains having at least 80% sequence identity. One of skill in the art would conclude that the specification fails to disclose a representative number of species to describe the claimed genera.
Owed to the variation among antibodies with respect to their CDRs, the structure of antibodies that correlates with their function, it is very difficult to provide adequate representation of a functionally defined antibody genus. There is unlikely to be any CDR structure shared by the entire genus, for example. Also, the disclosure of one set of antibody CDRs does not guide one of skill to the next set of CDRs. This is because it is well-known in this art that mutation of CDR residues leads to loss of antigen binding. 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 et al. (Proceedings of the National Academy of Sciences USA, Vol., 79, Pg. 1979-1983, 1982). Rudikoff et al. teach that the alteration of a single amino acid in the CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (Abstract). Thus, while applicant has described one or a few species within each of the genera recited, and the art may provide more, each genus is very large and would encompass antibody structures (CDR sets) that cannot be visualized from the prior art or instant disclosure. One of skill in this art cannot determine the antibody structures encompassed by the claimed genera only defined by function. Any future antibody structure may or may not be encompassed, and if it is, it would not have been represented in Applicant’s disclosed species. Thus, the described species cannot be considered representative of the recited genera of antibodies. E.g., AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014). Thus, the claims are rejected here.
As discussed above, an applicant may show that an invention is complete by disclosure of sufficiently detailed, relevant identifying characteristics which provide evidence that applicant was in possession of the claimed invention, i.e., complete or partial structure, other physical and/or chemical properties, functional characteristics when coupled with a known or disclosed correlation between function and structure, or some combination of such characteristics. Enzo Biochem, 323 F.3d at 964, 63 USPQ2d at 1613. Therefore, it is recommended that the instant claims be amended to recite complete structural information of the claimed antibodies that bind SARS-CoV-2 spike protein, including full CDRs, specific, and full-length heavy and light variable chain domains.
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, 7-9, 13, and 15 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “wherein the antibody: (a) comprises at least three CDRs of any one of the antibodies [..], 88, [..]; and/or (b) binds to the same epitope as or competes with antibody 159, 45 or 384”. The claim is indefinite because it is unclear which specific antibodies are being claimed. For instance, the antibody could be the 88th antibody listed in a prior art reference, or a specific antibody referred to as “88” in the instant specification or prior art. The same indefiniteness is present in part (b) of claim 1—it is unclear what “antibody 159, 45, or 384” means. Claims 2, 5, and 7 are also separately rejected because they specifically claim antibodies in this unclear manner.
The examiner notes that recitation of tables from the specification is not an appropriate manner to address this rejection. MPEP 2173.05(s) states:
Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience." Ex parte Fressola, 27 USPQ2d 1608, 1609 (Bd. Pat. App. & Inter. 1993) (citations omitted).
Reference characters corresponding to elements recited in the detailed description and the drawings may be used in conjunction with the recitation of the same element or group of elements in the claims. Generally, the presence or absence of such reference characters does not affect the scope of a claim. See MPEP § 608.01(m) for information pertaining to the treatment of reference characters in a claim.
Claims 2-5, 7-9, 13, and 15 are also rejected since they depend on claim 1, but do not remedy this deficiency.
Claim 1 recites “the antibody: (a) comprises at least three CDRs of any one of the antibodies [..] 88 [..]”. However, it is not apparent, based on the language of the claim, is the meaning of CDRs for antibody 88. For instance, the CDRs could be defined by the Kabat scheme or IMTG scheme, which have a very different sequence structure formats. It is also not clear if composite CDRs are encompassed, such as fusions of Kabat and IMGT CDRs. Thus, there are multiple structural interpretations of the claims. Claims 2-5, 7-9, 13, and 15 are also rejected since they depend on claim 1, but do not remedy this deficiency. Additionally, claims 2 and 4 recite CDRs of antibodies without proper clarification of the numbering scheme, and are also indefinite.
Regarding claim 4, which recites (j) a CDRH1, CDRH2, CDRH3, CDRL1, CDRL2, and CDRL3 having an amino acid sequence set forth in SEQ ID NOs: 105 to 110, respectively, the claim language “having an amino acid sequence” is interpreted to have multiple structural interpretations, and is thus indefinite. The limitation could mean that only partial CDR sequence is required, or it could mean that the full sequence is required. Accordingly, the metes and bounds of the claim are unclear, and the claim is rendered indefinite
See Ex parte Miyazaki, 89 USPQ2d 1207 (BPAI 2008) ("[R]ather than requiring that the claims are insolubly ambiguous, we hold that if a claim is amenable to two or more plausible claim constructions, the USPTO is justified in requiring the applicant to more precisely define the metes and bounds of the claimed invention by holding the claim unpatentable under 35 U.S.C. §112, second paragraph, as indefinite.").
Claim Rejections – Improper Markush Grouping
Claims 1-5, 7-9, 13, and 15 are rejected on the judicially-created basis that they contain 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).
The improper Markush grouping includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial structural feature and a common use that flows from the substantial structural feature for the following reasons:
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 the instant case, claim 1 recites an antibody capable of binding the spike protein of coronavirus SARS-CoV-2, wherein the antibody: (a) comprises at least three CDRs of [..] antibody 88 [..]; and/or (b) binds to the same epitope as or competes with antibody 159, 45, or 384, but they do not appear to share a substantial structural feature. The antibodies recited in part (a) of claim 1 represent an improper Markush group, as do the antibodies recited in part (b) of claim 1, for the same reason. Additionally, claims 3, 5, and 7 recite additional improper Markush groups of antibodies.
It is not even clear that the antibodies share the same function; even if they all bound spike protein, and shared that function, there is no maintained CDR set required to confer that function amongst them all. As demonstrated by the specification’s Table 1, these antibodies do not share CDRs, and to be a proper Markush group, the antibodies would need to share the entire set of CDRs. Thus, the antibodies represent improper Markush groups. Accordingly, a common use cannot flow from a shared substantial structural feature in these claims because said structural feature would be the CDR set. Since the instant claims contain Markush groups with members of antibodies that possess differing CDR sequences lacking shared, discernable, discrete domains associated with the claimed function of binding SARS-CoV-2 spike protein, the claims contain an improper Markush group and are rejected here. Regarding the improper Markush group of claim 1 (b), “binds to the same epitope as or competes with antibody 159, 45, or 384”, it is not even clear that these antibodies read on antibody 88. Claims 2-5, 7-9, 13, and 15 depend from claim 1 but do not introduce a proper Markush group for these issues.
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 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. 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 Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1, 8, and 15 are rejected under 35 U.S.C. 101 because
“Determining that a claim falls within one of the four enumerated categories of patentable subject matter recited in 35 U.S.C. 101 (i.e., process, machine, manufacture, or composition of matter) [..] does not end the eligibility analysis, because claims directed to nothing more than [..] natural phenomena, and laws of nature are not eligible for patent protection.” MPEP §2106.04(I).
In the instant case, the claims are directed to a category of patentable subject matter (a composition) recited in 35 U.S.C. §101, because they recite “an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody: (a) comprises at least three CDRs of antibody 88; and/or (b) binds to the same epitope as or competes with antibody 159, 45, or 384” (claim 1). However, this composition is naturally occurring in the blood of a subject. For the reasons described in the rejection under 35 U.S.C. §102 below, convalescent sera from COVID-19 patients, a natural product, reads on the claimed invention. Nielsen, et al. (Cell Host Microbe. 2020 Oct 7;28(4):516-525.e5) discloses that humoral responses are likely to be critical for the development of protective immunity to SARS-CoV-2, and neutralizing antibodies from convalescent COVID-19 patients have been reported, offering an important resource of potential protective or therapeutic antibodies (p. 516, col. 2, para. 1). The sera would inherently contain antibodies specific for every possible epitope of SARS-CoV-2 spike protein, because the sera came from convalescent individuals, which would mount a humoral response against each foreign spike protein antigen. Nielsen further discloses that among IgG+ B cells in COVID-19 patients, the proportion of IgG1+ cells was increased (p. 517, col. 2, para. 1). This convalescent sera would inherently comprise full-length antibodies comprising IgG1 constant regions (claim 8), and comprise at least one pharmaceutically acceptable diluent or carrier, such as water in the sera (claim 15). Along those lines, because circulating antibodies specific for SARS-CoV-2 would be present in the blood of those exposed to SARS-CoV-2, a composition comprising such antibodies would naturally occur in a subject exposed to SARS-CoV-2.
This judicial exception is not integrated into a practical application because claims 1, 8, and 15 do not recite additional elements that integrate the judicial exception into a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because there are no additional elements besides an exception. Since all claims read on sera from COVID-19 patients with natural immune reactions, any function of the claims would be found in the natural composition as well.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 1, 8, 15 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Nielsen, et al. (Cell Host Microbe. 2020 Oct 7;28(4):516-525.e5).
The claimed invention encompasses an antibody capable of binding to the spike protein of coronavirus SARS-CoV-2, wherein the antibody: (a) comprises at least three CDRs of antibody 88; and/or (b) binds to the same epitope as or competes with antibody 159, 45, or 384 (claim 1).
The Prior Art
Nielsen discloses that humoral responses are likely to be critical for the development of protective immunity to SARS-CoV-2, and neutralizing antibodies from convalescent COVID-19 patients have been reported, offering an important resource of potential protective or therapeutic antibodies (p. 516, col. 2, para. 1). Nielsen further discloses that among IgG+ B cells in COVID-19 patients, the proportion of IgG1+ cells was increased (p. 517, col. 2, para. 1). Claim 1 is indefinite for the reasons described above in the rejection under 35 U.S.C. §112(b), but regardless of the epitopes that antibody 88 and antibodies 159, 45, or 384 bind, Nielsen anticipates the claim because the sera would inherently contain antibodies specific for every possible epitope of SARS-CoV-2 spike protein, because the sera came from convalescent individuals, which would mount a humoral response against each foreign spike protein antigen. Nielsen also discloses that SARS-CoV-2 neutralizing serum antibodies are reported to be present in 67-90% of patients post-infection, depending on the severity of disease, neutralization assay, and threshold for positive results (p. 523, col. 1). The specification indicates that pharmaceutically acceptable carriers comprise aqueous carriers or diluents including water and saline (p. 77). In interpreting the broadest reasonable interpretation of the term “pharmaceutically acceptable diluent or carrier”, in the absence of specific definition in the specification, the examiner interprets “pharmaceutically acceptable diluent or carrier” to read on convalescent serum of a COVID-19 subject.
Therefore, claims 1, 8, and 15 are anticipated by Nielsen.
Conclusion
No claim is allowed. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JEFFREY MARK SIFFORD whose telephone number is (571)272-7289. The examiner can normally be reached 8:30 a.m. - 5:30 p.m. ET with alternating Fridays off.
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/JEFFREY MARK SIFFORD/Examiner, Art Unit 1671 /Michael Allen/Supervisory Patent Examiner, Art Unit 1671
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