Detailed Office 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 .
Status of the Claims
Acknowledgement is hereby made of receipt and entry of the communication filed 08 October, 2024. Claims 1-266 were canceled without prejudice or disclaimer and new claims 267-286 submitted.
37 C.F.R. § 1.98
The information disclosure statements filed 21 October, 2024, and 05 August, 2025, have been placed in the application file and the information referred to therein has been considered.
37 C.F.R. § 1.84
The drawings filed 23 January, 2024, are objected to because they are illegible (e.g., see Figs. 13A and 25A-C) or fail to comply with the sequence requirements (e.g., Figs. 8E, 13B, 25A/C, 36A-D, 47, and 48). Corrected drawing sheets in compliance with 37 C.F.R. § 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 C.F.R. § 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.
37 C.F.R. § 1.821-1.825
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 C.F.R. § 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 C.F.R. § 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 C.F.R. § 1.831-1.835. This "Sequence Listing XML" part of the disclosure may be submitted:
1. In accordance with 37 C.F.R. § 1.831(a) using the symbols and format requirements of 37 C.F.R. § 1.832 through 1.834 via the USPTO’s patent electronic filing system (Patent Center) (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/patents-application-process/filing-online/legal-framework-efs-web), 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 C.F.R. § 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 C.F.R. § 1.831(a) using the symbols and format requirements of 37 C.F.R. § 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 C.F.R. § 1.52(e)(1)(ii), labeled according to 37 C.F.R. § 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 C.F.R. § 1.52(e)(8) and 37 C.F.R. § 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.
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2) (e.g., see Figs. 8E, 13B, 25A/C, 36A-D, 47, and 48). However, this application fails to comply with the requirements of 37 C.F.R. § 1.821 through 1.825 for the reason(s) set forth below. Applicants are reminded that the sequence rules embrace all unbranched nucleotide sequences with ten or more bases and all unbranched, non-D amino acid sequences with four or more amino acids, provided that there are at least 4 “specifically defined” nucleotides or amino acids. The rules apply to all sequences in a given application, whether claimed or not. All such sequences are relevant for the purposes of building a comprehensive database and properly assessing prior art. It is therefore essential that all sequences, whether only disclosed or also claimed, be included in the database. See 37 C.F.R. § 1.821(a) and M.P.E.P. § 2421.02.
Sequences appearing in the drawings are not identified by sequence identifiers in accordance with 37 C.F.R. § 1.821(d). Sequence identifiers for sequences must appear either in the drawings or in the Brief Description of the Drawings. Applicant must provide:
- Replacement and annotated drawings in accordance with 37 C.F.R. § 1.121(d) inserting the required sequence identifiers;
AND/OR
- A substitute specification in compliance with 37 C.F.R. § 1.121(b)(3) and 1.125 inserting the required sequence identifiers 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.
35 U.S.C. § 112(b)
The following is a quotation of 35 U.S.C. § 112(b):
(b) CONCLUSION. —The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claim 275 is rejected under 35 U.S.C. § 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, regards as the invention. Two separate requirements are set forth under this statute: (1) the claims must set forth the subject matter that applicants regard as their invention; and (2) the claims must particularly point out and distinctly define the metes and bounds of the subject matter that will be protected by the patent grant. The claim references a method of preventing or treating a viral infection in a subject, wherein the viral infection is associated with a coronavirus. This recitation is confusing because it is not readily manifest if the patient is actually infected with a coronavirus or if the patient is dually infected with another virus (e.g., influenza) and a coronavirus. Moreover, is the target of treatment the coronavirus or another virus? Amendment of the claim language to reference a patient that is infected with a coronavirus would be remedial.
35 U.S.C. § 112(d)
The following is a quotation of 35 U.S.C. § 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 268, 274, and 281 are rejected under 35 U.S.C. § 112(d), as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. The claims are directed toward an antibody, method of treatment using said antibody, or pharmaceutical composition comprising said antibody, wherein said antibody comprises heavy/light chains that display up to 40% amino acid sequence variation with SEQ ID NOS.: 3 and 4. These claims depend from claims that comprise the CDRs of SEQ ID NOS.: 3 and 4. However, the amino acid sequence variation is not limited to any particular portion of SEQ ID NO.: 3 or 4. Thus, the variant sequences could have single or multiple substitutions in the CDRs, in which case they would not encompass the CDRs of SEQ ID NOS.: 3 or 4 and would not be further limiting. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
35 U.S.C. § 112(a)
The following is a quotation 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.
Written Description
Claims 267-286 are rejected under 35 U.S.C. § 112(a), 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, at the time the application was filed, had possession of the claimed invention. Amgen, Inc. v. Sanofi, 872 F.3d 1367, 124 U.S.P.Q.2d 1354 (Fed. Cir. 2017). AbbVie Deutschland GmbH & Co. v. Janssen Biotech, Inc., 759 F.3d 1285, 111 U.S.P.Q.2d 1780 (Fed. Cir. 2014). Univ. of Rochester v. G.D. Searle & Co., Inc., 358 F.3d 916, 920, 69 U.S.P.Q.2d 1886, (Fed. Cir. 2004). Enzo Biochem, Inc. v. Gen-Probe, Inc., 296 F.3d 1316, 63 U.S.P.Q.2d 1609, (Fed. Cir. 2002). Regents of the University of California v. Eli Lilly & Co., 119 F.3d 1559, 43 U.S.P.Q.2d 1398, (Fed. Cir. 1997). Fiers v. Revel Co., 984 F.2d 1164, 25 U.S.P.Q.2d 1601, (Fed. Cir. 1993). Amgen, Inc. v. Chugai Pharmaceutical Co., 927 F.2d 1200, 18 U.S.P.Q.2d 1016, (Fed. Cir. 1991). In re Rasmussen, 650 F.2d 1212, 211 U.S.P.Q. 323 (C.C.P.A. 1981). In re Wertheim, 541 F.2d 257, 191 U.S.P.Q. 90 (C.C.P.A. 1976).
The crux of the statutory requirement governing written description is whether one skilled in the art, familiar with the practice of the art at the time of the filing date, could reasonably have found the later claimed invention in the specification as filed. In re Kaslow, 707 F.2d 1366, 1375, 217 U.S.P.Q. 1089, 1096 (Fed. Cir. 1983). In re Wilder, 736 F.2d 1516, 1520 222 U.S.P.Q. 349, 372 (Fed. Cir. 1984, cert. denied, 469 U.S. 1209 (1985). Texas Instruments, Inc. v. International Trade Comm’n, 871 F.2d 1054, 1063, 10 U.S.P.Q.2d 1257, 1263 (Fed. Cir. 1989). Moreover, the courts have stated that the evaluation of written description is highly fact-specific, and that broadly articulated rules are inappropriate. In re Wertheim, 541 F.2d 257, 263, 191 U.S.P.Q. 90, 97 (C.C.P.A. 1976). In re Driscoll, 562 F.2d 1245, 1250, 195 U.S.P.Q. 434, 438 (C.C.P.A. 1977). It is also important to remember that the true issue in question is not whether the specification enables one of ordinary skill in the art to make the later claimed invention, but whether or not the disclosure is sufficiently clear that those skilled in the art will conclude that the applicant made the invention having the specific claim limitations. Martin v. Mayer, 823 F2d 500, 505, 3 U.S.P.Q.2d 1333, 1337 (Fed. Cir. 1987).
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 has possession of the claimed invention. See, e.g., Vas-Cath, Inc. v. Mahurkar, 935 F.2d at 1563, 19 U.S.P.Q.2d at 1116. An applicant shows possession of the claimed invention by describing the claimed invention with all of its limitations using such descriptive means as words, structures, figures, diagrams, and formulas that fully set forth the claimed invention. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572, 41 U.S.P.Q.2d 1961, 1966 (Fed. Cir. 1997). The claimed invention as a whole may not be adequately described where an invention is described solely in terms of a method of its making coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its function. A biomolecule sequence described only by a functional characteristic, without any known or disclosed correlation between that function and the structure of the sequence, normally is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence. A lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 U.S.P.Q.2d 1895, 1905 (Fed. Cir. 1996).
Determination of adequate written description requires the Examiner to read and analyze the specification for compliance with 35 U.S.C. § 112(a). In particular, each claim should be analyzed to determine its broadest reasonable interpretation consistent with written description. Each claim should be evaluated to determine if sufficient structures, acts, or functions are recited to make clear the scope and meaning of the claim, including the weight to be given the preamble. The entire application should be reviewed including the specific embodiments, figures, and sequence listings, to understand how applicant provides support for the various features of the claimed invention. The analysis of whether the specification complies with the written description requirement calls for the examiner to compare the scope of the claim with the scope of the description to determine whether applicant has demonstrated that the inventor was in possession of the claimed invention. Such a review is conducted from the standpoint of one of ordinary skill in the art at the time the application was filed (see, e.g., Wang Labs., Inc. v. Toshiba Corp., 993 F.2d 858, 865, 26 USPQ2d 1767, 1774 (Fed. Cir. 1993)) and should include a determination of the field of the invention and the level of skill and knowledge in the art. Finally, the Examiner should determine whether there is sufficient written description to inform a skilled artisan that the inventor was in possession of the claimed invention as a whole at the time of filing.
The claims are directed toward a broad genus of antibody variants that fail to receive adequate support in the specification. Claims 267, 273, and 280 are directed toward an engineered Mab comprising the complementarity determining regions (CDRs) of SEQ ID NOS.: 3 and 4. These correspond to the variable heavy (VH) and light (VL) chains, respectively. These claims only require the CDRs and do not specify the framework structure. With respect to claims 268, 274, and 281, the claims encompass variant antibody sequences that display upwards of 40% amino acid sequence variability compared to the parent sequence. Mab 10-40 contains the following structure (CDRs are bold-faced):
QLQLQESGPG LVKPSETLSL TCTVSGGSIS SSNFYWGWIR QPPGKGLEWI ASITYSGRTF
YNPSLKSRVA ISVDTSKNQF SLKLSSVTAA DTAVYYCART FPSYYDRSGY HYLNYGMDVW
GQGTTVTVSS (VH, SEQ 3); and
NFMLTQPHSM SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSSPTTVIY EDNQRPSGVP
DRFSGSIDSS SNSASLTISG LKTEDEADYY CQSYDSSSWV FGGGTKLTVL (VL, SEQ 4).
Thus, the claims encompass an inordinate number of antibody variants (~2 x 10105 for the heavy chain and ~1x 1089 for the light chains).1 However, the specification is deficient and fails to disclose the isolation, characterization, and utilization of any other Mab 10-40 variants. Moreover, it has been well-documented in the art that single or multiple amino acid insertions, deletions, or substitutions can abrogate antibody-antigen binding interactions (Winkler et al. (2000); Sela-Culang et al. (2013); Klein et al. (2013); Sirin et al. (2016)). Sela-Culang et al. (2013) clearly demonstrate that both the complementarity determining regions (CDRs) and framework regions (FRs) contribute to antigen-antibody binding interactions. Some positions within the CDRs never participate in antigen binding whereas other off-CDR residues are critical for the interaction. Moreover, the constant regions also play a role in antibody recognition and binding. Klein et al. (2013) examined the role of the FRs in viral neutralization and reported that this region requires somatic mutations to produce broadly neutralizing antibodies (bnAbs). Somatic mutations in the FRs enhanced the breadth and potency of bnAbs by providing increased flexibility and/or direct antigen contact. This study demonstrated that FRs play an essential role in antigen recognition and binding that goes well beyond a simple scaffolding mechanism. Winkler et al. (2000) noted that single amino acid substitutions in the CDR regions can alter antibody binding specificity. Finally, Sirin et al. (2016) review the challenges associated with the accurate prediction of the effect of mutations on antigen recognition and binding. As noted supra, the specification fails to describe the generation, isolation, and characterization of any Mab 10-40 variants. Moreover, the specification fails to identify those residues that are sine qua non for antigen recognition and binding.
Accordingly, when all the aformentioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicant was not in possession of a sufficient number of antibody variants to support the claim breadth currently sought.
Scope of Enablement
Claims 273-275, 278, and 279 are rejected under 35 U.S.C. § 112(a) or 35 U.S.C. § 112 (pre-AIA ), first paragraph, because the specification does not reasonably enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims. The claims are directed toward a method of treating or preventing a viral infection in a subject comprising administering a SARS-CoV-2 spike-specific monoclonal antibody. A method of treating a SARS-CoV-2 infection using an antibody comprising the VH and VL chains comprising SEQ ID NOS.: 3 and 4 would be acceptable. However, the claims are not enabled for the treatment and prevention of non-SARS-CoV-2 viral infections or treatment/prevention methods that do not utilize Mab 10-40.
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 quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art and the breadth of the claims. 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:
1) The claim breadth encompasses the treatment and prevention of a large number of viral infections. Viral infections could be the result, inter alia, of single-stranded RNA-RT viruses (e.g., HIV-1), single-stranded positive-sense RNA viruses (e.g., Poliovirus), single-stranded negative-sense RNA viruses (e.g., Ebolavirus), or double-stranded DNA viruses (e.g., Herpesviruses). These viruses are all genotypically and phenotypically distinct from coronaviruses, particularly SARS-CoV-2. These viruses infect different cell targets, recognize different cell-surface receptors, and utilize different replicative mechanisms. Thus, one skilled in the art would reasonably question the ability of an SARS-CoV-2-specific antibody as a generic therapeutic antiviral.
2) The claim breadth encompasses a large number of 10-40 antibody variants. The claims only require the CDRs and do not specify the framework structure. With respect to claim 274, the claim encompasses variant antibody sequences that display upwards of 40% amino acid sequence variability compared to the parent sequence. Mab 10-40 contains the following structure (CDRs are bold-faced):
QLQLQESGPG LVKPSETLSL TCTVSGGSIS SSNFYWGWIR QPPGKGLEWI ASITYSGRTF
YNPSLKSRVA ISVDTSKNQF SLKLSSVTAA DTAVYYCART FPSYYDRSGY HYLNYGMDVW
GQGTTVTVSS (VH, SEQ 3); and
NFMLTQPHSM SESPGKTVTI SCTRSSGSIA SNYVQWYQQR PGSSPTTVIY EDNQRPSGVP
DRFSGSIDSS SNSASLTISG LKTEDEADYY CQSYDSSSWV FGGGTKLTVL (VL, SEQ 4).
Thus, the claims encompass an inordinate number of antibody variants (~2 x 10105 for the heavy chain and ~1x 1089 for the light chains).2 However, the specification is deficient and fails to disclose the isolation, characterization, and utilization of any other Mab 10-40 variants.
3) The disclosure fails to provide adequate guidance with respect to the ability of a SARS-CoV-2-specific antibody to neutralize and prevent non-SARS-CoV-2 viral infections.
4) The disclosure fails to provide adequate guidance with respect to the effects of any given amino acid substitution, insertion, or deletion on Mab 10-40 antigen recognition and binding.
5) Generating antibody mutants that retain their original binding and neutralizing activity is an unpredictable undertaking. it has been well-documented in the art that single or multiple amino acid insertions, deletions, or substitutions can abrogate antibody-antigen binding interactions (Winkler et al. (2000); Sela-Culang et al. (2013); Klein et al. (2013); Sirin et al. (2016)). Sela-Culang et al. (2013) clearly demonstrate that both the complementarity determining regions (CDRs) and framework regions (FRs) contribute to antigen-antibody binding interactions. Some positions within the CDRs never participate in antigen binding whereas other off-CDR residues are critical for the interaction. Moreover, the constant regions also play a role in antibody recognition and binding. Klein et al. (2013) examined the role of the FRs in viral neutralization and reported that this region requires somatic mutations to produce broadly neutralizing antibodies (bnAbs). Somatic mutations in the FRs enhanced the breadth and potency of bnAbs by providing increased flexibility and/or direct antigen contact. This study demonstrated that FRs play an essential role in antigen recognition and binding that goes well beyond a simple scaffolding mechanism. Winkler et al. (2000) noted that single amino acid substitutions in the CDR regions can alter antibody binding specificity. Finally, Sirin et al. (2016) review the challenges associated with the accurate prediction of the effect of mutations on antigen recognition and binding.
6) The disclosure fails to provide any working embodiments demonstrating that Mab 10-40 variants were capable of binding to and neutralizing SARS-CoV-2. The disclosure also fails to demonstrate that Mab 10-40, or variants thereof, are capable of binding to and neutralizing any non-SARS-CoV-2 virus.
Accordingly, when all the aforementioned factors are considered in toto, the skilled artisan would reasonably conclude that Applicant’s teachings are insufficient to support the full breadth of patent protection currently sought.
Allowable Subject Matter
Monoclonal antibody (Mab) 10-40 appears to be free of the prior art of record. Amendment of the claim language to reference an isolated or purified Mab that is capable of binding to the SARS-CoV-2 spike (S) protein comprising the variable heavy chain of SEQ ID NO.: 3 and the variable light chain of SEQ ID NO.: 4 would be acceptable.
Correspondence
Any inquiry concerning this communication should be directed to Jeffrey S. Parkin, Ph.D., whose telephone number is (571) 272-0908. The Examiner can normally be reached Monday through Friday from 10:00 AM to 6:00 PM. A message may be left on the Examiner's voice mail service. Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice. If attempts to reach the examiner are unsuccessful, the Examiner's supervisor, Michael Allen, Ph.D., can be reached at (571) 270-3497. Direct general status inquiries to the Technology Center 1600 receptionist at (571) 272-1600.
Information regarding the status of an application may be obtained from the Patent Center. Status information for published applications may be obtained from the Patent Center. Status information for unpublished applications is available through the Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
Respectfully,
/JEFFREY S PARKIN/Primary Examiner, Art Unit 1671 05 September, 2026
1 These calculations were performed as follows: TV=(NY)(X!)/(Y!)((X-Y-1)!), wherein, TV=the total number of variant sequences, N=the number of amino acids or nucleotides that can be substituted (i.e., if any of the 20 naturally occurring amino acids can be substituted, N=19; if any of the four naturally occurring nucleotides can be substituted, N=3), Y=the number of amino acids/nucleotides in the parent sequence that can be substituted (i.e., if the amino acid sequence is 100 aa in length and 10% genetic variation is allowed, Y=10 [100@10%]), and X=the total sequence length of the sequence of interest.
2 These calculations were performed as follows: TV=(NY)(X!)/(Y!)((X-Y-1)!), wherein, TV=the total number of variant sequences, N=the number of amino acids or nucleotides that can be substituted (i.e., if any of the 20 naturally occurring amino acids can be substituted, N=19; if any of the four naturally occurring nucleotides can be substituted, N=3), Y=the number of amino acids/nucleotides in the parent sequence that can be substituted (i.e., if the amino acid sequence is 100 aa in length and 10% genetic variation is allowed, Y=10 [100@10%]), and X=the total sequence length of the sequence of interest.
Prosecution Insights