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 .
Preliminary Amendment
The preliminary amendment dated 02/05/2026 has been entered. Claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35, 37, 43 are pending and under examination.
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. The earliest possible effective filing date for the instant claims is September 15, 2020 based on the filing date of the provisional application 63/078,677.
Election/Restriction
Applicant’s species election in the reply filed on 02/05/2026 is acknowledged. Applicant elected:
- The CDR1, HV2, HV4, and CDR3 SEQ ID NOs: 265-325-355-295. Corresponding targeting moiety/composition that includes the CDR1, HV2, HV4, and CDR3 being: SEQ ID NO: 20 (ShAb20 nanobody).
- One single type of binding agent: VNAR.
- One SARS-CoV-2 strain to which the elected one single composition binds to: B.1.351.
- One single chimeric molecule comprising the elected single composition and one
single heterologous protein (claim 10 and 14): chimeric protein of SEQ ID NO: 102 (encoded by SEQ ID NO: 175) with the binding agent of SEQ ID NO: 20 and a Fc domain;
- One single linker identified by SEQ ID NO 208
- In the case of claim 18, one single multivalent construct with the all different
binding agents and one of them being the elected one single composition: SEQ ID NO 20 and a chimeric protein of SEQ ID NO: 108 (encoded by SEQ ID NO: 181) comprising the binding agent of SEQ ID NO 24 (comprising a CDR1 comprising SEQ ID NO: 269, a CDR3 comprising SEQ ID NO: 299, a HV2 comprising SEQ ID NO: 329, and a HV4 comprising SEQ ID NO: 359);
- One single nucleic acid sequence encoding the elected one single composition
and identified by SEQ ID NO. 50 (claim 3).
Applicant has identified the following claims: 1, 3, 6, 8, 10-12, 14, 17, 18, 22, 23, 26, 27, 30, 31, 35, and 37 readable on the elected species.
Claim 43 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as to being drawn to a non-elected species
Claims 1, 3, 6, 8, 10-12, 14, 17, 18, 22, 23, 26, 27, 30, 31, 35, and 37 are under examination for their full scope.
Nucleotide and/or Amino Acid Sequence Disclosures
REQUIREMENTS FOR PATENT APPLICATIONS CONTAINING NUCLEOTIDE AND/OR AMINO ACID SEQUENCE DISCLOSURES
Items 1) and 2) provide general guidance related to requirements for sequence disclosures.
37 CFR 1.821(c) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.821(a) must contain a "Sequence Listing," 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 1.821 - 1.825. This "Sequence Listing" part of the disclosure may be submitted:
In accordance with 37 CFR 1.821(c)(1) 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") as an ASCII text file, together with an incorporation-by-reference of the material in the ASCII text file in a separate paragraph of the specification as required by 37 CFR 1.823(b)(1) identifying:
the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(1) 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 of the material in the ASCII text file according to 37 CFR 1.52(e)(8) and 37 CFR 1.823(b)(1) in a separate paragraph of the specification identifying:
the name of the ASCII text file;
the date of creation; and
the size of the ASCII text file in bytes;
In accordance with 37 CFR 1.821(c)(2) via the USPTO patent electronic filing system as a PDF file (not recommended); or
In accordance with 37 CFR 1.821(c)(3) on physical sheets of paper (not recommended).
When a “Sequence Listing” has been submitted as a PDF file as in 1(c) above (37 CFR 1.821(c)(2)) or on physical sheets of paper as in 1(d) above (37 CFR 1.821(c)(3)), 37 CFR 1.821(e)(1) requires a computer readable form (CRF) of the “Sequence Listing” in accordance with the requirements of 37 CFR 1.824.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed via the USPTO patent electronic filing system as a PDF, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the PDF copy and the CRF copy (the ASCII text file copy) are identical.
If the "Sequence Listing" required by 37 CFR 1.821(c) is filed on paper or read-only optical disc, then 37 CFR 1.821(e)(1)(ii) or 1.821(e)(2)(ii) requires submission of a statement that the "Sequence Listing" content of the paper or read-only optical disc copy and the CRF are identical.
Specific deficiencies and the required response to this Office Action are as follows:
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (for example: Fig. 11A, 12, 17A, 19C) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for all nucleotide and/or amino acid sequences must appear either in the drawings or in the Brief Description of the Drawings.
Required response – Applicant must provide:
Replacement and annotated 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 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.
Claim Rejections – Improper Markush Grouping
2. Claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 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). A Markush grouping is proper if the alternatives defined by the Markush group (i.e., alternatives from which a selection is to be made in the context of a combination or process, or alternative chemical compounds as a whole) share a “single structural similarity” and a common use. A Markush grouping meets these requirements in two situations. First, a Markush grouping is proper if the alternatives are all members of the same recognized physical or chemical class or the same art-recognized class, and are disclosed in the specification or known in the art to be functionally equivalent and have a common use. Second, where a Markush grouping describes alternative chemical compounds, whether by words or chemical formulas, and the alternatives do not belong to a recognized class as set forth above, the members of the Markush grouping may be considered to share a “single structural similarity” and common use where the alternatives share both a substantial structural feature and a common use that flows from the substantial structural feature. See MPEP § 2117.
The Markush grouping of claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35, 37 are improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use that flows from the substantial structural feature for the following reasons:
Claim 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 are drawn to SARS-CoV-2 coronavirus binding agent comprising at least one targeting moiety, wherein the at least one targeting moiety comprises:
a) the amino acid sequence of SEQ ID NO: 1- SEQ ID NO: 30, or SEQ ID NO: 394, or an amino acid sequence having at least 90% sequence identity with one of SEQ ID NO: 1-SEQ ID NO: 30, or SEQ ID NO: 394; or
b) a complementarity determining region 1 (CDR1) and a CDR3. wherein the CDR1 comprises an amino acid sequence selected from any one of SEQ ID NO: 246-SEQ ID NO: 275. and SEQ ID NO: 395. and the CDR3 comprises an amino acid sequence selected from any one of SEQ ID NO: 276. SEQ ID NO: 301-SEQ ID NO: 305, and SEQ ID NO: 396,wherein the binding agent binds to a Spike glycoprotein of SARS-CoV-2 coronavirus.
The biding agents listed in the claims do not appear to be related to each other. The CDRs from this list of binding agents, which is known to be crucial for determining an antibody's binding activity and specificity, have very difference sequences (as an example see [00170] in the specification, sequence comparison between AliB5-2D8, MoB3-3D8, MoB5-1D4 as well as their corresponding CDR1, CDR3, HV2 and HV4 sequences. See Figure 1 below), and thus, they bind different epitopes. Each binding agent is distinct because the amino acid sequence confers unique structural, chemical, and functional characteristics. In addition, Rudikoff (Proc. Nat. Acad. Sci. USA Vol. 79, pp. 1979-1983, March 1982) teaches that even a single amino acid change on antibodies can alter binding specific (entire article). This would also be the case for antibodies derived from sharks which have enhanced specificity and affinity when compared to traditional antibodies as evidenced by Koenning (Scientific Reports volume 7, Article number: 9676 (2017) Introduction). Overall, vNAR domains possess two (CDR1 and CDR3) instead of three CDR loops. However, the lack of a CDR2 binding site is at least in part compensated by the elongated CDR3 region that mediates the major part of antigen-binding (page 2 second paragraph). Therefore, the claimed binding agents are different products/species.
Figure 1. Specification, page 60
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Although only a few binding agents are used here as an example, an artisan would understand that the sequence differences in the CDRs and HVs in all the potential binding agents listed in the claims would amount to structural differences in the binding region as a whole, and therefore there would be no structural similarity between the binding agents leading to be functionally equivalent and to their common use.
Lastly, while the claims recite “SARS-CoV-2 coronavirus binding agent” this is not an art-recognized class of molecules as defined in MPEP 2117 as: that it was known within the art that each member could be substituted one for the other, with the expectation that the same intended result (be functionally equivalent) would be achieved. Therefore, in the instant case, the structurally different antibodies are not art-recognized substitutions for each other.
Dependent claims are rejected for failing to resolve the improper Markush grouping.
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim 3 is rejected on the basis that it contains an improper Markush grouping of alternatives.
The Markush grouping of claim 3 is improper because the alternatives defined by the Markush grouping do not share both a single structural similarity and a common use for the following reasons:
Claim 3 is drawn to SARS-CoV-2 coronavirus binding agents, wherein the at least one targeting moiety is a full-length antibody, a single-domain antibody, a recombinant heavy-chain-only antibody (VHH), a single-chain antibody (scFv), a shark heavy- chain-only antibody (VNAR), a microprotein, a darpin, an anticalin, an adnectin, an aptamer, a Fv, a Fab, a Fab', a F(ab')2, a peptide mimetic molecule, a natural ligand for a receptor, or a synthetic molecules.
The claim comprises unrelated molecules, such as a full length antibody, a natural ligand for a receptor which would include other molecules that are not antibodies, synthetic molecules that could be anything that it is not a natural molecule. There is not a single structural similarity and a common use among these alternatives and no evidence that the alternatives are considered to be functionally equivalent and do not belong to a recognized class as set forth above,
To overcome this rejection, Applicant may set forth each alternative (or grouping of patentably indistinct alternatives) within an improper Markush grouping in a series of independent or dependent claims and/or present convincing arguments that the group members recited in the alternative within a single claim in fact share a single structural similarity as well as a common use.
Claim Rejections - 35 USC § 112
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, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 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 the limitation "A SARS-CoV-2 coronavirus binding agent comprising ….”. This limitation is unclear because the term “binding agent” is not defined as such in the specification. The closely related term "antigen-binding fragment" refer to “a part of an antibody molecule that comprises amino acids responsible for the specific binding between antibody and antigen” [0042], and the term “antibody” is defined as “an immunoglobulin or an antigen-binding fragment thereof. As will be understood by those in the art, the immunological binding reagents encompassed by the term "antibody" or "antibodies" extend to all antibodies from all species,…” [0040]. Therefore, claim 1 encompasses polyclonal, monoclonal, monospecific, bispecific, trispecific, quad-specific, polyspecific, shark, humanized, human, camelised, etc. [0040]. However, the structure and sequences recited in claim 1 and in all dependent claims can only be applicable to shark antibodies as evidenced by Koenning (Scientific Reports volume 7, Article number: 9676 (2017)). vNAR domains possess two (CDR1 and CDR3) instead of three CDR loops. However, the lack of a CDR2 binding site is at least in part compensated by the elongated CDR3 region that mediates the major part of antigen-binding (page 2 second paragraph). Dependent claims are rejected for failing to resolve the indefiniteness. Recitation’s clarity is improved by the following changes: adding “shark monoclonal nanobodies” to the limitation. So, the recitation reads: “A SARS-CoV-2 coronavirus shark monoclonal antibody comprising ….…….”.
Appropriate correction is required. 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.").
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.
Claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 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 enablement requirement. 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.
8. Claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for the elected monoclonal nanobody, (SEQ ID NO: 20 (ShAb20 nanobody); the CDR1, HV2, HV4, and CDR3 SEQ ID NOs: 265-325-355-295), binding to a Spike glycoprotein of SARS-CoV-2 coronavirus does not reasonably provide enablement for any kind of antibody (“antibody” refers to all antibodies from all species, and antigen binding fragments thereof [0040]) comprising at least 90% identical sequences to all the VH region, which also can comprise all the possible combinations of the CDRs that can be obtained when combining all the sequences listed in claim 1. 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 specification discloses the construction of VNAR phage display libraries (example 1) and antibody purification and characterization (example 2). Competition of nanobodies with SARS-CoV-2 antibody assays (page 61) ACE2 inhibition assays (page 62) and SARS-CoV-2 and SARS-CoV-1 pseudovirus neutralization assay (page 69) were performed. The VNARs were sequenced and the CDR1, CDR3, HV2 and NV4 were identified (Table 2 page 78). The elected species ShAb20 showed strong binding to SARS-CoV-1 RBD ([0031], Table 5).
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The claims are directed to a broad class of antibodies, only defined by its function “able to bind a SARS-CoV-2 spike protein”, with a partial structure at best. Claim 1 recites having at least 90% sequence identity and the changes could be found anywhere in the sequence including CDRs and HVs. However, the specification did not give the skilled in the art enough information to choose candidate antigen binding structures from the vast number of options of thousands of candidates, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
The specification discloses that the elected antibody ShAb20 showed strong binding to SARS-CoV-1 RBD ([0031], therefore, it is “able to bind a SARS-CoV-2 spike protein”.
In Amgen Inc. et al. v. Sanofi et al., 598 U.S. 594, 2023 USPQ2d 602 (2023), the Supreme Court held that claims drawn to a genus of monoclonal antibodies, which were functionally claimed by their ability to bind to a specific protein, PCSK9, were invalid due to lack of enablement. The claims at issue were functional, in that they defined the genus by its function (the ability to bind to specific residues of PCSK9) as opposed to reciting a specific structure (the amino acid sequence of the antibodies in the genus). The Supreme Court concluded that the patents at issue failed to adequately enable the full scope of the genus of antibodies that performed the function of binding to specific amino acid residues on PCSK9 and blocking the binding of PCSK9 to a particular cholesterol receptor, LDLR. This decision reaffirmed the prior decision made by the Federal District Court in Amgen Inc. v. Sanofi, Aventisub LLC., 987 F.3d 1080 (Fed. Cir. 2021).
The Court clarified that the specification does not always need to "describe with particularity how to make and use every single embodiment within a claimed class." Id. at 610-11. However, "[i]f a patent claims an entire class of processes, machines, manufactures, or compositions of matter, the patent’s specification must enable a person skilled in the art to make and use the entire class….The more one claims, the more one must enable." Id.
The specification may require a reasonable amount of experimentation to make and use the invention and what is reasonable will depend on the nature of the invention and the underlying art. For example, "it may suffice to give an example (or a few examples) if the specification also discloses some general quality … running through the class that gives it a peculiar fitness for the particular purpose" and "disclosing that general quality may reliably enable a person skilled in the art to make and use all of what is claimed, not merely a subset." Id. at 611 (internal quotations omitted). However, the Supreme Court found that Amgen failed to enable all that it claimed, even if allowing for a reasonable degree of experimentation. Id. at 613; see also Baxalta Inc. v Genentech, Inc., 81 F.4th 1362, 1367, 2023 USPQ2d 1103 (Fed. Cir. 2023) ("[t]he facts of this case are more analogous to—and are, in fact, indistinguishable from—those in Amgen. We do not interpret Amgen to have disturbed our prior enablement case law, including Wands and its factors."). Moreover, "[w]e see no meaningful difference between Wands' ‘undue experimentation’ and Amgen's ‘[un]reasonable experimentation’ standards. Id. at footnote 4. See also Guidelines for Assessing Enablement in Utility Applications and Patents in View of the Supreme Court Decision in Amgen Inc. et al. v. Sanofi et al., 89 FR 1563 (January 10, 2024), which explains that regardless of the technology the Wands factors should be used when assessing enablement.
However, while the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class which included "a ‘vast’ number of additional antibodies" that Amgen had not described by their amino acid sequences. Id. at 613. The Court found that Amgen sought to monopolize an entire class by their function, even though that class was much broader than the 26 exemplary antibodies disclosed by their amino acid structure. Id. at 613.
In Amgen Inc. v. Sanofi, Aventisub LLC, 987 F.3d 1080 (Fed. Cir. 2021), which the Supreme Court affirmed, the Federal Circuit explicitly applied the Wands factors to assess whether the specification of Amgen’s patent provided sufficient enablement, for purposes of 35 U.S.C. 112(a), to make and use the full scope of the claimed invention. The court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Id. at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. See also the following cases across various technology areas: McRO, Inc. v. Bandai Namco Games Am. Inc., 959 F.3d 1091, 2020 USPQ2d 10550 (Fed. Cir. 2020); Wyeth & Cordis Corp. v. Abbott Laboratories, 720 F.3d 1380, 107 USPQ2d 1273 (Fed. Cir. 2013); Enzo Life Sciences, Inc. v. Roche Molecular Systems, Inc., 928 F.3d 1340 (Fed. Cir. 2019); and Idenix Pharmaceuticals LLC v. Gilead Sciences Inc., 941 F.3d 1149, 2019 USPQ2d 415844 (Fed. Cir. 2019).
Amgen attempted to claim an entire class of compounds by their function, namely antibodies that bind to the “sweet spot” of PCSK9 thereby inhibiting it from binding to LDL, while only describing 26 amino acid sequences in its specification. The two processes, the “roadmap” and “conservative substitution” did not save Amgen. According to the Court, these amounted to “little more than two research assignments” which forced scientists to conduct “painstaking experimentation” to see what worked. (citing Incandescent Lamp). The Court therefore held that Amgen’s specification did not enable the claims.
This case is akin to the issue in Amgen Inc. v. Sanofi, Aventisub LLC, in which the court relied on evidence showing that the scope of the claims encompassed millions of antibodies and that it was necessary to screen each candidate antibody in order to determine whether it met the functional limitations of the claim. Sanofi-Aventisub at 1088. Consequently, the Federal Circuit concluded that there was a lack of enablement. While the specification in Amgen identified 26 exemplary antibodies that performed the claimed function by their amino acid sequences, the claims at issue were directed to a class that included “a ‘vast' number of additional antibodies” that Amgen had not described by their amino acid sequences. Id. at 1256. The Supreme Court found that Amgen sought to monopolize an entire class of antibodies by their function, which was much broader than the 26 exemplary antibodies disclosed by their amino acid structure.
The instant claims are directed to a class of antibodies that include “a ‘vast’ number of antibodies comprising all the combinations of the CDRs that can be obtained when CDR1 comprises any of the SEQ ID NO: 246-SEQ ID NO: 275. and SEQ ID NO: 395. and the CDR3 comprises any one of SEQ ID NO: 276. SEQ ID NO: 301-SEQ ID NO: 305, and SEQ ID NO: 396, with the antibody being at least 90% identical sequence and still be able to bind the spike protein, in which the instant specification fails to describe the amino acid sequences of. It would be necessary to first generate and then screen each candidate antibody and fragments thereof, with the recited function) to determine whether it met the functional limitations of “able to bind the SARS-CoV-2 spike protein”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
The instant specification does not disclose any common structural feature delineating which of the claimed antibodies will have the function of “able to bind the SARS-CoV-2 spike protein”, or how to distinguish structures with this function from structures without.
The instant claims simply direct skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the antigen binding CDRs they elected to disclose and that “[u]nder Amgen, such random trial-and-error discovery, without more, constitutes unreasonable experimentation that falls outside the bounds required by § 112(a).” Id. at *8, *10.
The Supreme Court’s 2023 decision in Amgen v. Sanofi, which mainly involves the enablement requirement, states that “where a patentee purports to invent an entire genus, it must enable the entire genus”; “disclosing how to produce some antibodies that perform a specified function is not equivalent to disclosing how to produce all such antibodies – and it is the latter that petitioners claim as their invention”; S. Ct.
Additionally, in its recent decision in Baxalta Inc. v. Genentech, Inc., No. 2022-1461, 2023 WL 6135930 (Fed. Cir. Sept. 20, 2023) the Federal Circuit found the facts of this case to be "materially indistinguishable from those in Amgen." Baxalta, 2023 WL 6135930, at *4. According to the Federal Circuit, claim 1 covers "millions of potential candidate antibodies" (id.) that bind to Factor IX/IXa and increase the procoagulant activity of Factor IXa. The court, however, noted that the specification discloses the amino acid sequence of just 11 of those antibodies. And like the roadmap in the patents at issue in Amgen, "the '590 patent's roadmap simply directs skilled artisans to engage in the same iterative, trial-and-error process the inventors followed to discover the [11] antibodies they elected to disclose." (Id.) Missing from the specification, according to the Federal Circuit, was "'a quality common to every functional embodiment' ... that would allow a skilled artisan to predict which antibodies will perform the claimed functions" (id.; quoting Amgen Inc. v. Sanofi., 598 U.S. 594, 614 (2023)), such as a common structural or other feature that would allow the antibodies to perform the claimed functions, or an explanation as to why the 11 antibodies do so and others do not. (Baxalta, 2023 WL 6135930, at *4). And the Federal Circuit was not persuaded by Baxalta's argument that its disclosed hybridoma-and screening process "predictably and reliably generates new claimed antibodies every time it is performed" (id.), because "it is undisputed that to practice the full scope of the claimed invention, skilled artisans must make candidate antibodies and screen them to determine which ones perform the claimed functions." (Id.).
The specification does not reasonably provide enablement to use the invention of claims 1, 3, 6, 8, 10-12, 14, 17-18, 21-23, 26-27, 30-31, 35 and 37 as they are currently written. The specification does reasonably provide enablement to make and use the invention discussed supra.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary, the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
In addition, any CDR mutation, which can happen when you recombine all these CDRs into different species is not predictable. This is evidenced by the fact that 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 (Proc Natl Acad Sci USA 1982 Vol 79 page 1979). Rudikoff teaches that the alteration of a single amino acid in a single CDR of a phosphocholine-binding myeloma protein resulted in the loss of antigen-binding function (entire article, Abstract).) Thus, all claims rejected above, which read on shark monoclonal nanobody with mixed and matched CDRs, which are mutated CDR sets, or nanobodies recited by percent identity without all parental CDRs being fixed, are rejected here as failing the enablement requirement.
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)).
Claims 31 and 35 Claims 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 treating a SARS-CoV-2 infection in a subject does not reasonably provide enablement for preventing a SARS-CoV-2 infection in a subject. 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 commensurate in scope with these claims.
Nature of the invention/Breadth of the claims. The claims are drawn to a method for treating or preventing SARS-CoV-2 coronavirus infection, comprising administering to a subject in need thereof an effective amount of a composition comprising the SARS-CoV-2 coronavirus binding agent of claim 1 or a chimeric protein comprising said SARS-CoV-2 coronavirus binding agent, wherein said composition optionally further comprises a pharmaceutically acceptable excipient.
State of the prior art/Predictability of the art. Applicant should note that the examiner is interpreting the term “preventing” as completely negating or precluding infection of the virus, as the term is generally known by one of ordinary skill in the art. At the outset, prevention of an infection is not possible, since it is understood to mean prevention of a single virion from infecting a single cell. An infection may be inhibited, but not entirely prevented. In fact, the mechanism by which the invention operates depends on an infection occurring post-immunization.
The claim method only requires the administration of a single binding agent (the elected antibody ShAb20) or a chimeric protein comprising ShAb20. However, the most successful compositions to prevent SARS-CoV-2 have been antibody cocktails instead of a single agent. Antibody cocktails are preferred because they significantly reduce the risk of the virus undergoing mutations and becoming resistant to the treatment as taught by Baum (Science. 2020 Aug 21;369(6506):1014-1018). Researchers often use combinations (cocktails) like Evusheld (tixagevimab and cilgavimab) or REGEN-COV (casirivimab and imdevimab).
Working examples. The disclosure does not include any working examples of a method for preventing an infection caused by SARS-CoV-2.
Guidance in the specification. The specification provides guidance toward the construction of VNAR phage display libraries (example 1) and antibody purification and characterization (example 2). Competition of nanobodies with SARS-CoV-2 antibody assays (page 61) ACE2 inhibition assays (page 62) and SARS-CoV-2 and SARS-CoV-1 pseudovirus neutralization assay (page 69) were performed. The VNARs were sequenced and the CDR1, CDR3, HV2 and NV4 were identified (Table 2 page 78). The elected species ShAb20 showed strong binding to SARS-CoV-1 RBD ([0031], Table 5).
Amount of experimentation necessary. In view of the breadth of the claims, the nature of the invention, the state of the art (the use of antibody cocktails), the limited guidance and working examples in the specification, and the low level of predictability (no evidence of preventing infection), it would require undue experimentation for one skilled in the art to use the claimed methods.
Claims 22, 23 and 26 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 isolated or purified nucleic acid does not reasonably provide enablement for said non-isolated nucleic acid which reads upon a transgenic animal or a transgene therein. 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 and/or use the invention commensurate in scope with these claims.
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). See also MPEP § 2164.01(a) and § 2164.04. 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:
Nature of the invention/Breadth of the claims. Applicant broadly claims a nucleic acid. Under broadest reasonable interpretation, the claims read 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.
State of the prior art/Predictability of the art. With respect to the un-isolated 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 in the art 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 and possible silencing of host genes, which result in undesirable phenotypes and/or additional health issues in the animal. 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 in the host. Viral vectors, such as Adeno-associated virus (AAV), adenovirus (AdV), and lentiviral/retroviral vectors, can transfer larger amounts of genetic information to a host, but some vectors cannot carry all the required genetic structures for proper expression (e.g. entire gene plus extensive regulatory elements) and certain viral vectors can cause uncontrolled, random integration, which increases the risk of tumorigenesis and inconsistent expression. (See e.g. National Academies of Sciences, Engineering, and Medicine; Division on Earth and Life Studies; Food and Nutrition Board; Board on Agriculture and Natural Resources; Committee on Heritable Genetic Modification in Food Animals. Heritable Genetic Modification in Food Animals. Washington (DC): National Academies Press (US); 2025 Apr 23. 3, Potential Hazards to Animals and Consumers.; Park F. Lentiviral vectors: are they the future of animal transgenesis? Physiol Genomics. 2007 Oct 22;31(2):159-73. Epub 2007 Aug 7.; Shakweer WME, Krivoruchko AY, Dessouki SM, Khattab AA. A review of transgenic animal techniques and their applications. J Genet Eng Biotechnol. 2023 May 9;21(1):55.). Therefore, the field of transgenics was and remains highly unpredictable.
Working examples/Guidance in the Specification. No working example of a transgenic animal is disclosed in the specification. The specification provides guidance towards the generation and use of {a/an isolated/purified non-isolated nucleic acid.
Amount of experimentation necessary. 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 clarify that the nucleic acid is not within a transgenic animal by utilizing the term "isolated" before the recitation of said nucleic acid. 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 the transgenes and transgenic animals commensurate in scope with the claimed invention with a reasonable expectation of success. Thus, the claims are rejected here.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to make and/or use the claimed products.
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.
Section 33(a) of the America Invents Act reads as follows:
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claim 26 is rejected under 35 U.S.C. 101 and section 33(a) of the America Invents Act as being directed to or encompassing a human organism. See also Animals - Patentability, 1077 Off. Gaz. Pat. Office 24 (April 21, 1987) (indicating that human organisms are excluded from the scope of patentable subject matter under 35 U.S.C. 101). Claim 26 recites, “A host cell comprising the nucleic acid molecule of claim 22.” This claim includes human organisms because the host cell is not isolated.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/BENJAMIN P BLUMEL/ Primary Examiner, Art Unit 1671
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