.DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s preliminary amendment filed July 23, 2024 has been received and entered.
Claims 3-4, 9, 66-67, 85, 87-88, and 93-96 have been amended.
Claims 5-8, 10-59, 61, 63-65, 71-84, 86, 89-92, 97-99, and 101-102 have been canceled.
Claims 1-4, 9, 60, 62, 66-70, 85, 87-88, 93-96, and 100 are pending and under consideration.
Priority
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of U.S. Application No. 18/313,306 filed May 5, 2023, which claims the benefit of U.S. Provisional Application Nos. 63/480,903 filed 01/20/2023, 63/478,650 filed 01/05/2023, 63/385,957 filed 12/02/2022, 63/383,695 filed 11/14/2022, 63/424,945 filed 11/13/2022, 63/381,132 filed 10/26/2022, 63/381,131 filed 10/26/2022, 63/364,331 filed 05/06/2022, and 63/364,328 filed 05/06/2022.
However, Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosures of the prior provisional applications fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a), first paragraph for one or more claims of this application.
The instant claims are drawn to a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus-2 spike glycoprotein (SARS-CoV-2-Spike), comprising an immunoglobulin heavy chain variable domain (VH) a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to a HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and an immunoglobulin light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to a LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
The specifications for provisional applications 63/480,903, 63/478,650, 63/385,957, 63/383,695, 63/424,945, 63/381,132, 63/381,131, 63/364,331, and 63/364,328 fail to disclose all of the amino acid sequences for the 51 instantly claimed antibodies.
The first occurrence of the VH and VL CDR amino acid sequences for instantly claimed antibodies AB-1 to AB-51 as recited in instant claim 2, is in the disclosure of parent application 18/313,306 filed May 5, 2023.
Should Applicant disagree with the examiner’s factual determination as to the disclosure of the various claim limitations, Applicant may point out the particular places within the provisional applications which discloses the specific subject matter.
Accordingly, the May 5, 2023 filing date of U.S. Application No. 18/313,306 will be used for the purpose of applying art.
Information Disclosure Statements
The seven information disclosure statements (IDSs) submitted on 7/23/2024 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 1-3, 9, 67-68, 88, and 100 are objected to because of the following informalities:
Claims 1-3, 9, 60, 62, and 100 recite SEQ ID NOs, however there should be a space in between the colon and the number, e.g., SEQ ID NO: 4.
Claim 1 recites “a HCDR1” and “a LCDR1”, however, the claim should read “an HCDR1” and “an LCDR1”.
Claim 2 – delete the comma after LCDR3.
Claim 2 recites ”…comprising the HCDR1, HCDR2 and HCDR3, and LCDR1, LCDR2 and LCDR3, of an antibody comprising an amino acid sequence selected from:”, however, it is suggested the claim be amended to read, “”…comprising the HCDR1, HCDR2, HCDR3, and LCDR1, LCDR2, and LCDR3 of an antibody comprising the amino acid sequences selected from:…”.
Claim 9 (part xx) – the embodiment is missing “or” after the semicolon.
Claims 67-68 recite “antigen binding” and “antigen-binding”, respectively. Applicant should amend so both claims recite the term with or without a hyphen.
Claim 88 – betacoronavirius is misspelled and should read “betacoronavirus”
Claim 88 recites ”a method of reducing infectivity of a betacoronavirus, such as SARS-CoV-2, of a cell in a subject…”, which is grammatically awkward. It is suggested the claim be amended to read ”a method of reducing infectivity of a betacoronavirus, such as SARS-CoV-2, in a cell of a subject…”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 1-4, 9, 60, 62, 66-70, 85, 87-88, 93-96, and 100 are 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.
Claim 1 is drawn to a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a heavy chain variable domain (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to a HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and a light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to a LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
Claim 100 recites a “polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a paratope that is substantially similar to a paratope of an antibody comprising an amino acid sequence selected from:…”.
The term “substantially similar to” is a relative term which renders the claims indefinite. The specification discloses the term “substantially similar to” refers to a polypeptide that is substantially similar in amino acid sequence (e.g., has at least about 80%, at least about 90%, at least about 95%, at least about 96%, at least about 97%, at least about 98%, or at least about 99% of the amino acid residues amino acid sequence identity) and substantially preserves one or more functional properties of a specified polypeptide disclosed herein. In some embodiments, the one or more functional properties are selected from, without limitation, a substantially similar binding affinity, a substantially similar binding specificity, a substantially similar inhibitory activity, a substantially similar neutralization activity, and a substantially similar self-association property [00112].
However, this disclosure does not provide a limiting definition, rather it only provides examples of when CDRs might be considered "substantially similar to".
Therefore, the term “substantially similar to” is not defined by the claims, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
For examination purposes, changes within a CDR that do not eliminate the antibody's binding to the target antigen will be considered to result in a CDR that is "substantially similar to" the recited CDR amino acid sequence.
Claims 60 and 62 only define the anti-SARS-CoV-2-Spike antibody VH amino acid sequence (SEQ ID NO: 2). Accordingly, claims 2-4, 60, 62, 66-70, 85, 87-88, and 93-96 are included in the rejection as they do not fully resolve the ambiguity.
Claims 2, 9, and 100 recite the VH/VL amino acid sequences (SEQ ID NOs) for the presently claimed antibodies, with the antibody name in parentheses (AB-1 to AB-51). However, the antibody name encompasses not only the variable regions, but also the constant regions and the particular form of the antibody (e.g., Fab or IgG1). For examination purposes, the claims will be interpreted as only requiring the sequences recited. It is suggested that Applicant delete the parenthetical clone designations from each claim to obviate this rejection.
Claim 88 recites the term “such as”, which renders the claims indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d). For the purpose of examination, SARS-CoV-2 is betacoronavirus infectivity that is reduced.
Claim 100 recites a “polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a paratope that is substantially similar to a paratope of an antibody comprising an amino acid sequence selected from:…”.
The specification discloses the amino acid residues of a paratope contribute to an antibody’s interaction with an epitope of its target protein. An interaction can be a hydrogen bond, a salt bridge, a van der Waals interaction, an electrostatic interaction, a hydrophobic interaction, pi-interaction effects, an ionic bond, and/or any combination thereof. An interaction can be direct, or indirect, e.g., via a coordinated intermediate molecule, such as an ion or water. The residues of a paratope, in some embodiments, comprise only residues that are part of a defined CDR. In some embodiments, the residues of a paratope further comprise one or more residues that are not part of a defined CDR (e.g., residues within a defined framework region) [00110].
The specification discloses that the paratope residues of antibodies comprising SEQ ID Nos: 4-48 and SEQ ID Nos: 51-76 are shown in Figs. 2 and 3, respectively.
The term “paratope” does not allow for the skilled person to determine the scope of the claims. The specification refers to the paratope only in terms of amino acid residues contributing to a binding interaction with an epitope of a target protein, which allows for amino acid sequences outside of the presently claimed CDRs. Further, figures 2-3 do not provide sufficient structural definition, as other FR regions may be encompassed by the term. As such, one of ordinary skill in the art would not be able to determine the paratope of the 51 presently claimed antibodies unless they are specifically defined.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
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.
WRITTEN DESCRIPTION
Claims 3-4, 60, and 62 are rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
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 MPEP § 2163.
Claims 3-4, 60, and 62 are drawn to a polypeptide that specifically SARS-CoV-2-Spike. However, the claims define the polypeptide (i.e., antibody) by the heavy chain variable domain (VH) or the light chain variable domain (VL).
Claim 3 discloses the VH has at least 85% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs: 4-48.
Claim 4 discloses the VL has at least 85% sequence identity to the amino acid sequence of any one or more of SEQ ID NOs: 51-76.
Claims 60 discloses the VH comprises the amino acid sequence of SEQ ID NO: 2.
Claim 62 discloses the VH comprises the amino acid sequence of SEQ ID NO: 2, wherein X1 is S, N, A, R, L or F; X2 is D or E; X3 is T or V; X4 is L or V; X5 is S, Q, R, K, Y, D or E; X6 is N, K, A, S, R or E; X7 is G, N or L; X8 is V, I, S or K; or X9 is Q, Y, K, F or H, or any combination of the foregoing.
Therefore, claims 3, 60, and 62 are drawn to an anti-SARS-CoV-2-Spike polypeptide VH paired with any VL, while claim 4 is drawn an anti-SARS-CoV-2-Spike polypeptide VL paired with any VH.
However, none of the claims provide all 6 CDRs for the recited anti-SARS-CoV-2-Spike polypeptide.
Additionally, claims 3-4 allow for up to 15% variability in the VH and VL, respectively. The specification discloses that the VH and/or VL amino acid sequences may comprise at least 1 amino acid substitution relative to the parent amino acid sequence. For example, the number of amino acid substitutions can be at least about: 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19 or 20, or about: 1-20, 1-19, 2-19, 2-18, 2-17, 3-17, 3-16, 4-16, 4-15, 5-15, 5-14, 6-14, 6-13, 7-13, 7-12, 8-12, 8-11 or 9-11. In some embodiments, the at least 1 amino acid substitution replaces only a HCDR1, a HCDR2 and/or a HCDR3 residue.
Claims 60 and 62 limit the VH to SEQ ID NO: 2, however claim 62 allows for changes at 9 amino acid residues. Consequently, it can be considered that the inventions defined by claims 3-4, 62, and 65 encompass countless possible substitutions.
Therefore, the claims encompass a large genus of binding molecules that bind SARS-CoV-2-Spike, comprised of different combinations of heavy and light chain amino acid sequences, respectively, which represent structurally distinct polypeptides. The state of the art is such that antibody variable regions are composed of a heavy and light chain, each involved in providing for binding specificity. Variability in the antigen binding site is achieved by V(D)J recombination via heavy and light chain pairing, with the most diverse regions being the 6 CDR regions in the heavy and light chain. As taught by Janeway et al. (2001), the antibody repertoire in humans is at least 1011, with a large degree of diversity in both heavy and light chains. See also Rabia et al. (2018; pg. 4), which teaches that the maximal chemical diversity of antibody CDRs is unimaginably large and is extremely challenging to define the sequence determinant of antibody specificity.
Examples of antigen-binding polypeptides comprising only a VH (or less commonly, a VL) that in turn comprise only three CDRs certainly do exist in the literature, but those polypeptides generally comprise unique structures such as CDR1 and CDR3's that are elongated in length and that are often disulfide linked (De Genst et al., 2006; cited IDS 7/23/2024). "Shuffling" of the VL (or less commonly the VH) had also been used to improve affinity of a parent antibody in certain instances. But the procedure generally required a "dominant" VH (i.e., a VH that is primarily responsible for antigen specificity (Yoshinaga et al., 2008; cited IDS 7/23/2024).
The Specification describes production of antibody variants of a reference antibody that was isolated from a person with COVID-19 and shown to bind SARS-CoV-2-Spike protein [00362]. The reference antibody was an IgG1 human antibody comprising the VH set forth in SEQ ID NO: 3 and the VL set forth in SEQ ID NO: 50. Applicant prepared a variant set of 182 sequences, gathered information regarding the functional activities of those variants, and then selected seed molecules for production of a new variant set of 364 antibodies [00366]. The top performing antibodies were then selected for additional characterization, including AB-1, which has the VH set forth in SEQ ID NO: 4 and the VL set forth in SEQ ID NO: 51. While applicant provides considerable additional data regarding the functional properties of AB-1, none of the polypeptides are described in the specification as having the function of binding SARS-COV-2-Spike with only a VH or only a VL. Instead, all of the antibodies contain a VH and VL pair.
Thus, one cannot readily extrapolate the properties of the polypeptide represented by claims 3-4, 60, and 62, as the properties of the polypeptides are not predictive of the full genus of proteins that can be generated. While a number of variant sequences have been described, neither the specification nor the prior art has established that a VH or a VL falling within the scope of the claims can pair with a wide variety of other VL or VH, respectively, so that the VH by itself, or VL by itself, could be considered an identifying characteristic of the polypeptide.
It is well established in the art that the formation of an intact antigen-binding site generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three complementarity determining regions (CDRs) which provide the majority of the contact residues for the binding of the antibody to its target epitope. Sela-Culang et al. (Fron lmmunol, 2013; 4:302) teaches six CDRs are widely assumed to be responsible for antigen recognition lie within each variable domain. 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 [Abstract, pg. 1].
Based on the state of the art, a full antibody binding site comprising six hypervariable loops (CDRs) within the VH and VL domains (with three CDRs on the heavy chain and three CDRs on the light chain), are required for SARS-CoV-2-Spike binding. While the CDRs of the claimed invention are intended to SARS-CoV-2-Spike for the treatment of betacoronavirus infection, artisans would not be able to envision the other CDR sequences or other variable domain based on recitation of the VH or VL amino acid sequences that would bind and inhibit SARS-CoV-2-Spike.
Indeed, recent court decisions including AbbVie Deutschland GmbH v. Janssen Biotech. Inc. 759 F.3d 1285 (Fed. Cir. 2014) and Amgen v. Sanofi, (Fed Cir, 2017-1480. 10/5/2017) have clearly indicated that identification of the antigen or epitope to which an antibody binds is insufficient to provide adequate written description for antibodies binding said antigen or epitope. Additionally, when claiming a broad genus of antibodies, the accompanying specification should include a description of diverse species across the scope of genus. As illustrated by the AbbVie decision, a description of even 300 representative species may not be sufficient to satisfy the written description requirement if all 300 representative species are structurally and functionally similar.
Therefore, the claimed genus of anti-SARS-CoV-2-Spike binding polypeptides lacks adequate written description because the claims fail to recite all six CDRs for the instantly claimed anti-SARS-CoV-2-Spike binding polypeptides. Thus, one of ordinary skill in the art would reasonably conclude that the applicant was not in possession of the full breadth of the claimed genus of anti-SARS-CoV-2-Spike binding polypeptides at the time the instant application was filed.
ENABLEMENT
Claims 87-88 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for treating a subject having COVID-19 and reducing the infectivity of a SARS-CoV-2 infection by administering an effective amount of AB-1 (SEQ ID NOs: 4 and 51), AB-15 (SEQ ID NOs: 17 and 61), and AB-17 (SEQ ID NOs: 6 and 63); does not reasonably provide enablement for treating a subject having COVID-19 and reducing the infectivity of a SARS-CoV-2 infection with any of the other instantly claimed antibodies.
The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
(1) The nature of the invention and (5) The breadth of the claims:
Claims 87-88 are drawn to treating COVID-19 and reducing infectivity of SARS-CoV-2 infections with a polypeptide comprising an HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and an LCDR1, LCDR2, and LCDR3 that are substantially similar to a LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
Regarding treating COVID-19 and other betacoronaviruses in general, Val-Chum et al. (WO 2022/140845; cited IDS 7/23/2024) (“Val-Chum”) teaches SARS-CoV-2, the etiologic agent of COVID-19, will become endemic in the population. The current pandemic is aggravated by the apparition of variants of concern that are feared to result in an antigenic drift that could evade vaccine-elicited immune responses. Thus, there is a need for the development of therapies that elicit neutralizing activity against SARS-CoV-2, including SARS-CoV-2 variants [pg. 2, lines 28-33]. To this end, Val-Chum isolated several mAbs isolated from COVID-19-infected patients that could bind SARS-CoV2 S2P, SARS-CoV2 RBD and SARS-CoV1 S2P variants [pg. 52, lines 32-33]. Several mAbs (identified as Mab#1-Mab#9, Mab#11-Mab#13, Mab#17, Mab#20-Mab#23, Mab#25, Mab#27, Mab#35-Mab#39, and Mab#41-Mab#48) were found to have neutralizing activity against SARS-CoV-2. One antibody, Mab#25, had the ability to neutralize additional SARS-CoV-2 variants of concern (VOCs). In contrast, Mab#30 showed reduced potency against 2 VOCs, and no neutralizing activity against WIV1 [pg. 53, lines 20-23].
Given the lack of predictability in generating antibodies that can neutralize SARS-CoV-2 and other VOCs, one of skill in the art would have to engage in undue experimentation to identify what anti- SARS-CoV-2-Spike antibodies would be effective in treating betacoranaviruses, including COVID-19.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant specification sets forth in vitro examples testing the ability of 364 antibody variants for optimal binding, neutralization, and developability profiles. Among these, 3 antibodies (AB-17, AB-15 and AB-1) were selected and used to test in additional neutralization assays (SARS-CoV-2 BA.2, BA.2.12.1 and BA.4/5 VSV-dG; SARS-CoV-2 Delta, SARS-CoV-1 and WIV1 pseudotyped lentiviruses) and benchmarked against the Reference Antibody. AB-17, AB-15 and AB-1 exhibited increased neutralization potency and efficacy compared to the Reference Antibody across all neutralization assays. They also showed neutralization activities greater than (SARS-CoV-2 BA.2, BA.2.12.1 and BA.4/5 VSV-dG) or comparable to (SARS-CoV-2 Delta, SARS-CoV-1 and WIV1) Sotrovimab [00365].
The neutralization activity of AB-1 was further validated in a hamster model of SARS-CoV-2 Delta challenge and SARS-CoV-2 Omicron BA.2 challenge [00377]. Overall, these results demonstrate that AB-1 has robust neutralizing activity against SARS-CoV-2 variants in vitro and in vivo [00379].
Therefore, the only embodiment that is enabled is treatment of COVID-19 and reducing infectivity of SARS-CoV-2 infections with antibodies AB-1, AB-15, and AB-17. One of skill in the art would be required to engage in extensive, difficult experimentation to develop antibodies that neutralize SARS-CoV-2 Spike which is known to be unpredictable as indicated above. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for treatment of COVID-19 and reducing infectivity of SARS-CoV-2 infections with the 51 instantly claimed antibodies as broadly claimed. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
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, 3-4, 60, 62, 66-70, 85, 87-88, and 93-96 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural product without significantly more.
Claim 1 is drawn to a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a heavy chain variable domain (VH) amino acid sequence comprising a heavy chain complementarity determining region 1 (HCDR1), a heavy chain complementarity determining region 2 (HCDR2) and a heavy chain complementarity determining region 3 (HCDR3) that are substantially similar to an HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and a light chain variable domain (VL) amino acid sequence comprising a light chain complementarity determining region 1 (LCDR1), a light chain complementarity determining region 2 (LCDR2) and a light chain complementarity determining region 3 (LCDR3) that are substantially similar to an LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
The claims recite a polypeptide that binds SARS-CoV-2-Spike and comprises a heavy chain variable domain and a light chain variable domain amino acid sequences that encompass the human antibody defined by SEQ ID NO: 3 and SEQ ID NO: 50 (reference antibody).
The specification discloses that VH amino acid sequence represented by SEQ ID NO: 3 is 100% identical to the VH amino acid sequence comprising SEQ ID NO: 3 of the reference antibody [Table 1, pg. 154]; while sequence analysis of the VL amino acid sequence represented by SEQ ID NO: 56 shows that it shares 99.3% identity to the VL of the reference antibody comprising SEQ ID NO: 50.
The specification further discloses that the reference antibody is a human IgG1 anti-S2 antibody isolated from a convalescent donor and showed neutralization of coronaviruses of the Sarbecovirus subgenus with promising neutralization potencies [368].
Val-Chum et al. (WO 2022/140845; cited IDS 7/23/2024) (“Val-Chum”) describes the identical antibody, Mab#25, comprising VH and VL amino acid sequences SEQ ID NO: 35 and SEQ ID NO: 36 that are 100% identical to the reference antibody encompassed by SEQ ID NO: 3 and 50 of the present application. Val-Chum teaches multiple naturally occurring antibodies were obtained from humans recovering from infection with SARS-CoV-2, including Mab#25 [Example 1, pg. 51]. Mab#25 was shown to bind SARS-CoV-2-spike from multiple viral variants [Example 3, pg. 53; Fig. 8].
Therefore, SEQ ID NO: 3 and SEQ ID NO: 50 define a naturally occurring antibody that falls within the scope of claims 1, 3-4, 60, 62, 66-70, 85, 87-88, and 93-96 that was isolated directly from a human patient. This is evidence that the reference antibody encompassing SEQ ID NO: 3 and SEQ ID NO: 50 appears in nature and therefore the claimed invention appears to be a product that is not markedly different in structure from naturally occurring products.
This judicial exception is not integrated into a practical application because at least one antibody encompassed within the breadth of the claims includes the same amino acid sequence and the same functional activity. The dependent claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because they are directed to the antibody per se, to compositions that do not alter the nature of the antibody to make it markedly different, or to an encoding polynucleotide generically that also include polynucleotides expressed by patient B cells, which would also be a product of nature. See MPEP 2106, Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 591-94, 106 USPQ2d 1972, 1979-81 (2013); Roche Molecular System, Inc. v. CEPHEID, 905 F.3d 1363, 1371, 128 USPQ2d 1221, 1227 (Fed. Cir. 2018).
Accordingly, the claims are directed to a judicial exception. Because the claim does not include any additional features that could add significantly more to the exception, the claim does not qualify as eligible subject matter under 35 U.S.C §101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-4, 62, 66-70, 85, 87-88, 93-96, and 100 are rejected under 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2) as being anticipated by Val-Chum et al. (WO 2022/140845; cited IDS 7/23/2024) (“Val-Chum”). This reference qualifies as prior art under both 35 U.S.C. 102(a)(1) and 35 U.S.C. 102(a)(2).
The instant claims are drawn to a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a VH amino acid sequence comprising an HCDR1, HCDR2, and HCDR3 that are substantially similar to an HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and a VL amino acid sequence comprising an LCDR1, LCDR2, and LCDR3 that are substantially similar to an LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
Val-Chum teaches neutralizing monoclonal antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their use in treating infection with the betacoronaviruses, including treating COVID-19 [Abstract]. Val-Chum teaches multiple naturally occurring antibodies that were obtained from humans recovering from infection with SARS-CoV-2 [Example 1, pg. 51]. The ability of Mab#25 to neutralize additional SARS-CoV-2 variants of concern Alpha (B.1.1.7), Delta (B.1.617.2) and Gamma (P.1), and a more distantly related SARS-like bat coronavirus, WIV1, was assessed. Mab#25 neutralized all variants and WIV1 with comparable potency [Example 3, pg. 53; Fig. 8]. The amino acid sequence of the heavy chain variable (VH) region and light chain variable region (VL) of Mab#25 are presented in Fig. 7F (below) [claim 4, embodiment (i)].
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Mab#25 VH as set forth in SEQ ID NO: 35 (Db) is 100% identical to instant SEQ ID NO: 3 (Qy).
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Mab#25 VL as set forth in SEQ ID NO: 36 (Db) is 100% identical to instant SEQ ID NO: 50 (Qy).
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Regarding claim 1, Mab#25 is a polypeptide (antibody) that binds SARS-CoV-2-Spike that comprises a VH with CDRs that are "substantially similar to” one or more of SEQ ID NOS: 4-48 and a VL with CDRs that are "substantially similar to” one or more of SEQ ID NOS: 51-76.
For example, instant VH SEQ ID NO: 4 (Qy) is 97.5% identical to Mab#25 VH SEQ ID NO: 35 (Db) with only 3 amino acid differences in the CDRs.
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Similarly, instant VL SEQ ID NO: 51 (Qy) is a VL that has only a single AA difference in LCDR3 and is 98.7% identical to Mab#25 VL SEQ ID NO: 36 (Db).
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As noted in the rejection under 35 U.S.C. 112(b), the metes and bounds of "substantially similar to" CDRs is ambiguous, but given the limited number of changes relative to Mab#25 VH and VL and the fact that both antibodies bind SARS-CoV-2-Spike, Mab#25 taught by Val-Chum anticipates the polypeptide of instant claim 1.
Regarding claims 2 and 100, Mab#25 is also a polypeptide as recited in claims 2 and 100 because claims 2 and 100 only require that the polypeptide comprises the CDRs of an antibody comprising "an" amino acid sequence selected from various sequences defined by SEQ ID NO and Mab#25 comprises instantly recited SEQ ID NO: 3 recited in claims 2 and 100.
Regarding claims 3-4, as noted above, the VH and VL of Mab#25 is over 95% identical to each of SEQ ID NO: 4 and SEQ ID NO: 51, respectively, so that claims 3-4, which recite a VH and VL at least 85% identical, are also anticipated.
Regarding claim 62, SEQ ID NO: 35 (Db) of Mab#25 is identical to the consensus sequence of instant SEQ ID NO: 2 (Qy) when X1 is S, X2 is D, X3 is T, X4 is L, X5 is S, X6 is N, X7 is G, X8 is V, and X9 is Q.
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Regarding claim 66, Mab#25 is a human antibody and therefore it contains human framework regions [claim 7].
Regarding claims 67-68, Val-Chum teaches IgG1 antibodies or fragments thereof [claim 8]. The disclosure defines antibody fragments as Fab, Fab', F(ab')2, and Fv fragments [pg. 28, lines 8-9].
Regarding claims 69-70, Val-Chum teaches the antibody can be an IgG1 antibody [claim 8], which necessarily includes heavy constant regions and light chain constant regions.
Regarding claim 85, Val-Chum teaches a pharmaceutical composition comprising the antibody and a pharmaceutically acceptable excipient [claim 17].
Regarding claim 87, Val-Chum teaches a method for preventing or treating a betacoronavirus infection or a related disease in a subject in need thereof, the method comprising administering to the subject an effective amount of the antibody or antigen binding fragment thereof [claim 21]. The title of the invention disclosed by Val-Chum is “Neutralizing Monoclonal Antibodies Against Covid-19”.
Regarding claim 88, Val-Chum teaches a method for reducing the risk of developing a betacoronavirus-related disease or the severity of a betacoronavirus-related disease in a subject, the method comprising administering to the subject an effective amount of the antibody or antigen binding fragment thereof, or the pharmaceutical composition, the method comprising blocking the entry of a betacoronavirus comprising contacting the cell and/or the virus with an effective amount of the antibody or antigen binding fragment thereof, or the pharmaceutical composition, wherein the betacoronavirus is a sarbecovirus, SARS-CoV-2 [claims 22-25].
Regarding claim 93, Val-Chum teaches a conjugate comprising the antibody or antigen binding fragment thereof [claim 10].
Regarding claims 94 and 96, Val-Chum teaches a nucleic acid comprising a sequence encoding the light and heavy chain of the antibody or antigen binding fragment thereof, and a host cell comprising the nucleic acid(s) [claims 11-12].
Therefore, the teachings of Val-Chun anticipate the instantly claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
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.
Claim 95 is rejected under 35 U.S.C. 103 as being unpatentable over Val-Chum et al. (WO 2022/140845; cited IDS 7/23/2024) (“Val-Chum”).
The instant claims are drawn to a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike), comprising a VH amino acid sequence comprising an HCDR1, HCDR2, and HCDR3 that are substantially similar to an HCDR1, HCDR2 and HCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 4-48; and a VL amino acid sequence comprising an LCDR1, LCDR2, and LCDR3 that are substantially similar to an LCDR1, LCDR2 and LCDR3, respectively, of the amino acid sequence of any one of SEQ ID NOs: 51-76.
The teachings of Val-Chum are set forth above.
In addition to Val-Chum disclosing a nucleic acid comprising a sequence encoding the light and heavy chain of the antibody or antigen binding fragment thereof, and a host cell comprising the nucleic acid(s) [claims 11-12]. Val-Chum also teaches the nucleic acid may be inserted into a vector and maintained in a host cell. After introduction of the expression vector, transformants which stably express a recombinant antibody are selected by culturing them in a medium for animal cell culture [pg. 39, par. 1; pg. 40, lines 12-14].
The instantly claimed invention is anticipated by Val-Chum as set forth above. It would have been obvious to one of ordinary skill in the art that a nucleic acid sequence can be inserted into an expression vector and introduced into a host cell wherein the host cell is induced to express the recombinant polypeptide, as these methods are routine in the art as evidenced by Val-Chum.
Therefore, the invention as a whole was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Statutory Double Patenting
A rejection based on double patenting of the “same invention” type finds its support in the language of 35 U.S.C. 101 which states that “whoever invents or discovers any new and useful process... may obtain a patent therefor...” (Emphasis added). Thus, the term “same invention,” in this context, means an invention drawn to identical subject matter. See Miller v. Eagle Mfg. Co., 151 U.S. 186 (1894); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Ockert, 245 F.2d 467, 114 USPQ 330 (CCPA 1957).
A statutory type (35 U.S.C. 101) double patenting rejection can be overcome by canceling or amending the claims that are directed to the same invention so they are no longer coextensive in scope. The filing of a terminal disclaimer cannot overcome a double patenting rejection based upon 35 U.S.C. 101.
Claims 1-4, 9, 60, 62, 66-70, 85, 87-88, 93-96, and 100 are rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-10, 12-16, 20, 22, 26, and 28-30 of U.S. Patent No. 11,993,644.
Patented claims 1-6 recite the VH and VL CDRs and full length amino acid sequences of a polypeptide that specifically binds a severe acute respiratory syndrome coronavirus 2 Spike glycoprotein (SARS-CoV-2-Spike) comprising the amino acid sequences encompassing the antibody defined by VH amino acid sequence of SEQ ID NO: 4 and VL amino acid sequence of SEQ ID NO: 51. Patented claim 7 recites the polypeptide an antigen-binding fragment of an antibody comprising a single-chain fragment variable (scFv), a fragment antigen binding (Fab ), a Fab' or a F(ab')2. Patented claim 8 recites the polypeptide comprises an antibody heavy chain constant domain, an antibody light chain constant domain, or both an antibody heavy chain constant domain and an antibody light chain constant domain. Patented claims 9-10 and 12-14 are drawn to the antibody heavy chain IgG1 constant domain and the light chain constant domain. Patented claim 15 recites a composition comprising the polypeptide of claim 1 and one or more pharmaceutical excipients, diluents, or carriers. Patented claims 16, 20, 22, and 26 are drawn to a method of treating a subject in need thereof, comprising administering an effective amount of the composition to the subject, wherein the subject has COVID-19, is suspected of having COVID-19, or is at risk of developing COVID-19; a method of reducing infectivity of a betacoronavirus in a subject in need thereof, comprising administering an effective amount of the composition to the subject. Patented claims 28-30 are drawn to a polynucleotide comprising a nucleotide sequence encoding the polypeptide, a host cell comprising the polynucleotide, and a method of making the polypeptide comprising culturing a host cell comprising a nucleotide sequence encoding the polypeptide under conditions where the polypeptide is expressed in the host cell.
The patented VH amino acid sequence of SEQ ID NO: 4 and the VL amino acid sequence of SEQ ID NO: 51 are 100% identical to AB-1 of the presently claimed invention comprising VH and VL amino acid sequences of SEQ ID NO: 4 and SEQ ID NO: 51, respectively.
This is a statutory double patenting rejection.
Claims 1-4, 9, 60, 62, 66-70, 85, 87-88, 93-96, and 100 are provisionally rejected under 35 U.S.C. 101 as claiming the same invention as that of claims 1-11, 14-21, 25-28, and 33-43 of copending U.S. Patent Application No. 19,129,517.
Copending claim 1 is drawn to a polypeptide comprising a heavy chain variable (VH) domain comprising an HCDR1, an HCDR2, and an HCDR3 having 100% sequence identity to an HCDR1, an HCDR2, and an HCDR3, respectively, of a VH domain set forth in Table 1 or Table 4; and a light chain variable (VL) domain comprising an LCDR1, an LCDR2, and an LCDR3 having 100% sequence identity to an LCDR1, an LCDR2, and an LCDR3, respectively, of a VL domain set forth in Table 2 or Table 4. Copending claims 2-4, 6-7, 14-17, and 33-38 further recite the CDRs and/or VH and VL sequences for AB-1 to AB-51. Copending claim 5 recites the polypeptide is humanized and/or contains human framework regions. Copending claims 8-9 recite the antibody can be a fragment, such as a single-chain fragment variable (scFv), a variable heavy domain of heavy chain (VHH), a fragment antigen-binding (Fab), a Fab', or F(ab)2. Copending claims 9-11 recite the heavy chain constant domain is an IgG1 antibody heavy chain constant domain. Copending claim 18 recites the antibodies specifically bind betacoronavirus Spike glycoprotein (SARS-CoV-2-Spike). Copending claims 19-21 are drawn to the polynucleotide(s) conjugated to a heterologous polypeptide sequence. Copending claims 25-27 are drawn to a nucleotide sequence encoding the polypeptide, a host cell comprising the polynucleotide, a method of making the polypeptide, comprising culturing a host cell comprising a nucleotide sequence encoding the polypeptide under conditions where the polypeptide is expressed in the host cell. Copending claim 28 recites a composition comprising the polypeptide or polynucleotide. Copending claim 39 recites the composition further comprises one or more pharmaceutical excipients, diluents, and/or carriers. Copending claim 40 is drawn to a method of treating a subject in need thereof, comprising administering an effective amount of the polypeptide, the polynucleotide, or the composition. Copending claim 41 is drawn to a method of reducing infectivity of SARS-CoV-2 of a cell in a subject, comprising contacting the cell with an effective amount of the polypeptide or the composition. Copending claims 42-43 recite the subject is a human that has COVID-19, is suspected of having COVID-19, or is at risk of developing COVID-19.
The copending claims recite the identical VH and VL amino acid sequences for the 51 presently claimed antibodies.
This is a provisional statutory double patenting rejection.
Conclusion
No claim is allowed.
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAUREEN DRISCOLL whose telephone number is (571)270-0730. The examiner can normally be reached Monday through Friday.
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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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