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 09/25/2025 has been entered. Claims 1-17, 19, 24-25 are pending. Claims 18, and 20-23 are cancelled.
Information Disclosure Statement
The submitted Information Disclosure Statement(s) (IDS) are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has/have been considered by the examiner.
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 August 8, 2020 based on the filing date of the Japanese application JP2020-143055
Applicant provided an English translation for JP2020-143055. Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application JP2021-054387must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Election/Restriction
Applicant’s election with traverse of Group I in the reply filed on 09/25/2025 is acknowledged.
Claims 15-17 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected product. Multiple products (Groups I and II) are claimed and there is no unity of invention between products. See 37 CFR 1.475 (c). and therefore, restriction is proper.
Applicant’s species election: Applicants elects the antibody 9-105 having:
- the heavy chain: CDR1 (SEQ ID NO: 9); CDR2 (SEQ ID NO:10); and CDR3 (SEQ ID NO: 11) and
- the light chain CDR1 (SEQ ID NO: 19); CDR2 (SEQ ID NO: 20) and CDR3 (SEQ ID NO: 21).
Applicant did not elect the corresponding heavy and light variable regions for these elected CDRs (identified by SEQ ID NOs), one single type of antibody and one single mutation in SARS-CoV-2 strain as requested in the restriction requirement. However, table 1 in the specification lists antibody 9-105 as having a VH comprising SEQ ID NO: 1 and a VL comprising SEQ ID NO; 5.
Claims 4-6 and 8-10 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected species.
Claims 1-3, 7, 11-14, 19, 24-25 are under examination.
The traversal filed by the Applicant is on the grounds that the present claims for Group I and III are unified and there is no unity of invention between product (group I) and method (group III, claims 24-25) have been fully considered and are found persuasive.
The requirement is now deemed proper and is therefore made FINAL.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
There are the hyperlinks https://doi.org/10.1101/2021.01.25.428137 and https://doi.org/10.1101/2021.01.25.428137 in the spec at paras[0007] and [0017], respectively
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 – 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:
i) the name of the ASCII text file;
ii) the date of creation; and
iii) the size of the ASCII text file in bytes;
Required response – Applicant must provide:
A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3) and 1.125 inserting the required incorporation-by-reference of the material 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.
Specific deficiency – Nucleotide and/or amino acid sequences appearing in the drawings (Figure 1-2) are not identified by sequence identifiers in accordance with 37 CFR 1.821(d). Sequence identifiers for 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 - 35 USC § 112 – Improper Markush Grouping
Claims 1-3, 19 and 24-25 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 1-2, 19 and 24-25 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:
The antibodies have distinct amino acid sequences and different epitopes as explained below.
The claims recite discrete antibody binding domains do not all share significant structural similarity. 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).
In the instant case, the group of antibodies of the claims contain species with different CDR sets. It is well established in the art that the formation of an intact antigen-binding site of antibodies generally requires the association of the complete heavy and light chain variable regions of a given antibody, each of which consists of three CDRs or hypervariable regions, which provide the majority of the contact residues for the binding of the antibody to its target epitope (Paul, Fundamental Immunology, 3rd Edition, 1993, pp. 292-295, under the heading “Fv Structure and Diversity in Three Dimensions”). The amino acid sequences and conformations of each of the heavy and light chain CDRs are critical in maintaining the antigen binding specificity and affinity, which is characteristic of the immunoglobulin. It is expected that all of the heavy and light chain CDRs in their proper order and in the context of framework sequences which maintain their required conformation, are required in order to produce a protein having antigen-binding function and that proper association of heavy and light chain variable regions is required in order to form functional antigen binding sites (Paul, page 293, first column, lines 3-8 and line 31 to column 2, line 9 and lines 27-30)
The following sequences constitute the HCDR3 regions of claim 1 which share no significant structural similarity:
heavy chain CDR3 of SEQ ID NO: 11 (ARDLEEAGGMDV),
heavy chain CDR3 of SEQ ID NO: 13 (ARPIVGARAGMDV),
heavy chain CDR3 of SEQ ID NO: 16 (ARDKNEGAMDV),
heavy chain CDR3 of SEQ ID NO: 18 (ARSYGDYFIDY),
Although only HCDR3 is used as an example, an artisan would understand that the sequence differences in the CDRs overall would amount to structural differences in the antibody binding region as a whole, and therefore there would be no structural similarity between the antibodies leading to be functionally equivalent and to their common use.
While the claims recite “an antibody or antigen binding fragment thereof that binds to the Receptor Binding Domain (RBD) present in the spike protein of the coronavirus (SARS-CoV-2), is capable of neutralizing the SARS-CoV-2 virus and can also be used in methods of preventing/treating SARS CoV-2” 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. However, claim 12 (drawn to the antibody or antigen-binding fragment thereof showing neutralizing activity against at least one SARS-CoV-2 mutant strain selected from the group consisting of B.1.1.7 mutant strain, mink cluster 5 mutant strain, B.1.351 mutant strain, P.1 mutant strain, P.3 mutant strains, B.1.617 mutant strain, R.1 mutant strain, and B.1.427/B.1.429 mutant strains) and claim 13 (drawn to the antibody showing neutralizing activity against a SARS-CoV-2 mutant strain having one or more mutations selected from the group consisting of K417T/N, E484K, N501Y, and L452R mutations) indicate that the antibodies listed in claims 1 and 2 can bind to different epitopes found in different strains and different mutations in some strain.
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.
Claim 3 is included in this rejection because the CDR numbering system (IMGT, Kabat, or Chothia) used to generate the CDRs has not been identified within the claims and CDRs from different numbering systems share different structural characteristics (please see Rejection 112(b) below),
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 and 7 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.
Claims 1-3 recite CDRs and claim 7 recite the SEQ ID NOs of the VH and VL. While the sequence and CDR positions are claimed, it would be unclear to a skilled artisan if they are infringing on the metes and bounds of the claim since the exact numbering system utilized to generate the CDRs is not claimed, nor is the entire VH/VL of the antibody which provided the basis for said CDRs present within the claim. The issue arises in that the exact numbering system for the CDRs is not identified in the claims, so it is unclear as to the metes and bounds of the claimed antibody. Since only the sequence of the CDR and position of the CDR is claimed and not the antibody numbering system utilized to identify said CDR, it would be unclear to a skilled artisan if they are infringing on the metes and bounds of the claim. It is required that the numbering system used for the CDRs be identified within the claim to ensure the correct antibody with the correct function is being claimed and is clear to one of skill in the art.
For instance, Figure 6 of Dondelinger et. al. (Dondelinger M, et. al. Front Immunol. 2018 Oct 16;9:2278.) illustrates the issue. If a sequence of SEQ ID NO: 1 is provided for the VH chain, the CDRs would be different depending on what numbering system is used. Say the claims are drawn to an antibody that consists of a CDR1 of SEQ ID NO: 3 (SGSAMH) (CDR identified with Martin numbering and Contact definition schema), wherein the longer antibody sequence is that of SEQ ID NO:1. Using a program or online tool such as AbRSA (http://cao.labshare.cn/AbRSA/abrsa.php) or NovoPro (https://www.novoprolabs.com/tools/cdr), a skilled artisan can identify the CDR regions in a longer antibody sequence that at least consists of a variable heavy (VH) or variable light (VL) chain complete sequence.
Under Chothia numbering, an antibody with a VH of SEQ ID NO:1 would have its CDRs identified as the following:
EVQLVETGGGVVRPGRSLRLSCTTSGFSFSGSAMHWVRQAPGKGLEWVAVISHDGNIIQYHDSVKGRFTISRDNSKNVLLLQMNSLRVDDTAMYYCARDVWLLPATISYAFDFWGQGTMVTVSS
Under Kabat numbering, an antibody with a VH of SEQ ID NO:1 would have its CDRs identified as the following:
EVQLVETGGGVVRPGRSLRLSCTTSGFSFSGSAMHWVRQAPGKGLEWVAVISHDGNIIQYHDSVKGRFTISRDNSKNVLLLQMNSLRVDDTAMYYCARDVWLLPATISYAFDFWGQGTMVTVSS
As one can see, the antibody with a VH of SEQ ID NO:1 under Kabat numbering has a CDR1 which consists of GSAMH, while the CDR1 using Chothia numbering consists of GFSFSGS. Neither therefore would be infringing upon the antibody with a CDR1 that consists of SGSAMH, even though all three of these sequences were found within the same VH region of the same antibody. Therefore, providing the CDR sequences without providing the numbering system used to identify said sequences within the claim is insufficient, as one of skill in the art is not clear as to the metes and bounds of the claimed invention.
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, 14, 19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claims 1-2, 14, 19 are drawn to an antibody, or antigen binding fragment thereof, that binds to the Receptor Binding Domain (RBD) present in the spike protein of SARS-CoV-2, and is capable of neutralizing the SARS-CoV-2 virus, comprising the following heavy chains HCDR1-3 and light chains LCDR1-3:region, wherein HCDR1 consists of SEQ ID NOs: 9, 12, 14 and 17, HCDR2 consists of SEQ ID NOs: 10 and 15, HCDR2 consists of SEQ ID NOs: 11, 13, 16 and 18, LCDR1 consists of SEQ ID NOs: 19, 22, 25 and 28, LCDR2 consists of SEQ ID NOs: 20, 23 and 26, LCDR3 consists of SEQ ID NOs: 21,24, 27 and 29. In addition, all these CDRS can consist of a sequence in which one or two amino acids are deleted, substituted or added in any of the CDRs, and any CDR can have 90% or more substantial identity with any the CDR. This antibody, or antigen-binding fragment thereof, selected from the group consisting of immunoglobulin molecules, monoclonal antibodies, human antibodies, chimeric antibodies, CDR-grafted antibodies, Fab, Fab', F(ab')2, Fd, Fv, disulfide-bound Fv, scFv, single domain antibodies, nanobody antibodies, diabody antibodies, bispecific antibodies, and multi-specific antibodies. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier.
Claim 3 is drawn to the antibody or antigen-binding fragment thereof according wherein the HCDR1 is SEQ ID NO:9, the HCDR2 is SEQ ID NO:10, the HCDR3 is SEQ ID NO:11, the LCR1 is SEQ ID NO: 19, the LCDR2 is SEQ ID NO: 20, and LCDR3 is SEQ ID NO:1.
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming. Therefore, the claims are drawn to a genus of “antibodies or antigen-binding fragment thereof“ for which there is inadequate written description.
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 (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claim is a recitation of requisite activity “able to bind SARS-CoV-2 RBD and is capable of neutralizing the SARS-CoV-2 virus“. There is not even identification of any particular portion of a structure that must be conserved for said activity. Regarding the genus of the claims the specification describes about 4 species within the genus claimed (Table 1, Figures 1 and 2). From the specification, it is clear that Applicant is in possession of species of these 4 antibodies. The claims, however are not limited to those species but also includes any combination of the HCDR1, HCDR2, HCDR3, LCDR1, LCDR2, LCDR3 with at least 90% identity to the corresponding CDRs and with sequence in which one or two amino acids are deleted, substituted or added in any of the CDRs. Therefore, the number of such antibodies could be in the thousands.
Claim 3 is included in this rejection because the CDR numbering system (IMGT, Kabat, or Chothia) used to generate the CDRs has not been identified within the claims and CDRs from different numbering systems share different structural characteristics (please see Rejection 112(b) above),
The specification fails to provide a representative number of species within the recited genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species, the specification does not provide adequate written description of the claimed genus.
Claims 1-3, 7, 14, 19, 24-25 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. .
In making a determination of whether the application complies with the written description requirement of 35 U.S.C. 112, first paragraph, it is necessary to understand what Applicant has possession of and what Applicant is claiming.
Claims 1-3, 7, 14, 19, 24-25 recites “antibody or a binding fragment thereof,” that is capable of preventing or treating a coronavirus in a subject comprising administering to the subject an effective amount of the antibody or antigen-binding fragment thereof according to claim 1 and a pharmaceutically acceptable carrier, which encompasses a genus of agents., Claims 1 recitation has been described above recite. Claims 2-3, 7, 14, 19, 24-25 are dependent from Claim 1 and do not materially limit the genus of agents, especially regarding the function of the antibody as being capable of preventing or treating a coronavirus in a subject and are therefore included in the rejection. These claims do not require that the genus of the claims possess any particular structure or other distinguishing feature that is characteristic of the genus as a whole. Therefore, the claims are drawn to a genus of “antibody or antigen-binding fragment thereof” for which there is inadequate written description.
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 (see MPEP 2163(II)(3)(a)(i)(A), reduction to drawings MPEP 2163(II)(3)(a)(i)(B), 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 MPEP 2163(II)(3)(a)(i)(C).
In the instant case, the only identifying characteristic present in the claims is a recitation of requisite activity (------------------capable of preventing or treating a coronavirus in a subject). There is not even identification of any particular portion of a structure that must be conserved for said activity in any coronavirus. Regarding the genus of the claims the specification describes no specific species within the genus claimed. From the specification, it is clear that Applicant is not in possession of species. The claims, however are not limited to those species but also includes thousands of antibodies and binding fragments thereof and the specification fails to provide a representative number of species within the recited genus. The Federal Circuit case AbbVie Deutschland v. Janssen (2014), invalidated AbbVie's broad genus claims for failing the written description requirement. The court held the patent didn't adequately describe the full scope of the claimed antibodies, requiring either a clear structure-function correlation or a representative set of examples across the claimed genus, not just a few starting points. For genus claims in unpredictable fields like antibodies, the specification must show either: (1) a strong structure-function correlation, explaining how structure dictates function across the genus or (2) a representative number of examples that demonstrate the full scope of the claimed genus. The ruling established stricter standards for functional genus claims, particularly for antibodies, requiring more detailed structural descriptions or numerous examples to support broad claims.
Further, CDRs may vary depending on the numbering system utilized. The Chothia, Kabat, Martin, IMGT, Honneger, and Gelfand numbering schemes all differ, and depending on the numbering system utilized, one may end up with wildly different antibodies with functional differences distinct from the original antibody (See e.g. Dondelinger M, Filée P, Sauvage E, Quinting B, Muyldermans S, Galleni M, Vandevenne MS. Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278.) These results highlight the pitfalls in attempting to describe an antibody functionally and/or with a percent identity to known structural characteristics.
Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, or representative number of species that are capable of preventing or treating a coronavirus in a subject, the specification does not provide adequate written description of the claimed genus/invention.
Claims 1-3, 11-14 19 and 24-25 are rejected under 35 U.S.C. 112(a) because the specification, while being enabling for the VH of SEQ ID NO: 1 and VL of SEQ ID NO: 2, they do NOT have support for any antibody with any CDR of SEQ ID NOs: 9, 10, 11 (CDRS 1-3 of heavy chain) and SEQ ID NOs: 19, 20, 21 (CDRS1-3 of light chain) with the percent identity and/or potential mutations claimed that will perform the claimed function of SARS CoV-2 viral neutralization and can also be used in methods of preventing/treating SARS CoV-2. In addition, CDRs may vary depending on the numbering system utilized. The Chothia, Kabat, Martin, IMGT, Honneger, and Gelfand numbering schemes all differ, and depending on the numbering system utilized, one may end up with wildly different antibodies with functional differences distinct from the original antibody (See e.g. Dondelinger M, Filée P, Sauvage E, Quinting B, Muyldermans S, Galleni M, Vandevenne MS. Understanding the Significance and Implications of Antibody Numbering and Antigen-Binding Surface/Residue Definition. Front Immunol. 2018 Oct 16;9:2278.) These results highlight the pitfalls in attempting to describe an antibody functionally and/or with a percent identity to known structural characteristics.
Further, all these CDRS can consist of a sequence in which one or two amino acids are deleted, substituted or added in any of the CDRs, and any CDR can have 90% or more substantial identity with any the CDR. This antibody, or antigen-binding fragment thereof, selected from the group consisting of immunoglobulin molecules, monoclonal antibodies, human antibodies, chimeric antibodies, CDR-grafted antibodies, Fab, Fab', F(ab')2, Fd, Fv, disulfide-bound Fv, scFv, single domain antibodies, nanobody antibodies, diabody antibodies, bispecific antibodies, and multi-specific antibodies. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof and a pharmaceutically acceptable carrier. All the claimed antibodies are not enabled for the claimed function of SARS CoV-2 viral neutralization and can also be used in methods of preventing/treating SARS CoV-2 (claims 24-25),. has a high neutralizing ability expressed as 50% inhibitory concentration (IC50 ug/ml) in a range from about 0.001ug/ml to about 1ug/ml (instant claim 11), showing neutralizing activity against at least one SARS-CoV-2 mutant strain selected from the group consisting of B.1.1.7 mutant strain, mink cluster 5 mutant strain, B.1.351 mutant strain, P.1 mutant strain, P.3 mutant strains, B.1.617 mutant strain, R.1 mutant strain, and B.1.427/B.1.429 mutant strains (instant claim 12), or showing neutralizing activity against a SARS-CoV-2 mutant strain having one or more mutations selected from the group consisting of K417T/N, E484K, N501Y mutation, and L452R mutations .
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. In the instantly claimed invention, the wide breadth of the different antibodies, and antigen binding fragments thereof (resulting in several thousands of potential binding proteins), would cause a skilled artisan to have to perform an undue amount of experimentation on the extremely large amount of possible permutations encompassed by said claims in order to determine if the method as claimed is enabled
The specification discloses that the 9-105 antibody is able to neutralize a pseudovirus expressing the SARS-CoV-2 spike protein on the cell surface and able to neutralize cells infected with pseudoviruses having the spikes of SARS-CoV-2 mutant strains (B.1.1.7 strain, B.1.351 strain, P.1 strain, mink cluster 5 strain).
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, or antigen-binding fragments thereof, only defined by its function “binds to the Receptor Binding Domain (RBD) present in the spike protein of SARS-CoV-2, is capable of neutralizing the SARS-CoV-2 virus and can also be used in methods of preventing/treating SARS CoV-2”, with a partial structure at best. 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 millions 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 only discloses one functional 9-105 antibody having VH as SEQ ID NO: 1 and VL as SEQ ID NO: 5: with the function of “binds to the Receptor Binding Domain (RBD) present in the spike protein of SARS-CoV-2, is capable of neutralizing the SARS-CoV-2 virus and can also be used in methods of preventing/treating SARS CoV-2”.
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, or antigen-binding fragments thereof, that include “a ‘vast’ number of additional antigen binding structures, 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 “binds to the Receptor Binding Domain (RBD) present in the spike protein of SARS-CoV-2, is capable of neutralizing the SARS-CoV-2 virus and can also be used in methods of preventing/treating SARS CoV-2”. 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 antigen binding structures to the Receptor Binding Domain (RBD) present in the spike protein of SARS-CoV-2, is capable of neutralizing the SARS-CoV-2 virus and can also be used in methods of preventing/treating SARS CoV-2 or how to distinguish structures with this function from structures without. The only structure-function relationship guidance the specification provides is the 9-105 antibody having VH as SEQ ID NO: 1 and VL as SEQ ID NO: 5.
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, 11-14, 19 and 24-25 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.
Conclusion
No claims are allowed.
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/IMMA BARRERA/
Examiner, Art Unit 1671
/RACHEL B GILL/Primary Examiner, Art Unit 1671