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 .
Priority
Acknowledgment is made of applicant's claim for priority under 35 U.S.C. 119(a)-(d) or (f), 365(a) or (b), or 386(a) based upon Application No. CN 202111529152.7 filed on December 14, 2021.
Information Disclosure Statement
The information disclosure statements (IDSs) submitted on January 19, 2024 and April 30, 2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDSs are being considered by the examiner.
Claim Status
Claims 1-11 and 13-16 are under consideration in this office action.
Claim Objections
Claim 5 is objected to because of the following informalities: in line 6, the term “wherein” should precede the limitation “the linker is a peptide or a polypeptide”. Appropriate correction is required.
Claim Interpretation
Claim 6 recites “human antibodies”. Based on this language, the antibodies of claims 1-6 are interpreted to be isolated from a human and are, therefore, a natural product.
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 1-6 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a
judicial exception (i.e. a law of nature, a natural phenomenon, or an abstract idea) without significantly
more. Claims 1-6 is drawn to a naturally occurring human antibody. The claims do not include
additional elements that are sufficient to amount to significantly more than the judicial exception
because they claim human framework regions and CDRs from a human immunoglobulin against SARS-CoV-2 spike protein. This fully human antibody is isolated from a human and is therefore a product produced by nature, the applicant has merely isolated it.
Guidance effective December 16, 2014 sets out a series of steps and factors for determining subject eligibility in light of recent court decisions including Association for Molecular Pathology v. Myriad Genetics, Inc., Mayo Collaborative Services v. Prometheus Laboratories, Inc., and Alice Corporation Pty. Ltd. v. CLS Bank International, et al. See gpo.gov/fdsys/pkg/FR-2014-12-16/pdf/2014-29414.pdf.
The first step under this guidance is determining if the claim is directed to one of the four statutory categories (process, machine, manufacture, or composition of matter). In this case, the claims are directed to a composition of matter.
The second step is determining if the claims recite or involve judicial exceptions, such as laws of nature, natural phenomena, or natural products. In this case, the claims involve natural products, the fully human antibodies that bind to SARS-CoV-2 spike protein comprise of HCDR1-3 of SEQ ID NO: 30 or 46 and LCDR1-3 of SEQ ID NO: 32 or 48.
In the next step, it must be determined if the claim as a whole amounts to something significantly more than the judicial exception. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Claims 1-6 fail to include any limitations that would distinguish the claimed antibodies from those which occur in nature. See Cao et al, published July 9 2020 (instant PTO-892), which teaches that autoantibodies to SARS-CoV-2 spike protein have been isolated from the B cells of convalescent COVID-19 patients (see abstract). Because the claimed CDR sequences are naturally occurring and the claims are not limited to antibody structures that are markedly different from the antibody isolated from humans, these claims are directed to a natural product.
In the absence of the hand of man, naturally occurring products are considered nonstatutory subject matter. Specifically, the claims, as written, do not sufficiently distinguish over the antibodies that exist naturally because the claims do not particularly point out any non-naturally occurring differences between the claimed products and the naturally occurring products. There is no specific limitation in the instant claims that would distinguish the claimed antibodies from the naturally occurring antibodies. Humanized antibodies and recombinant antibody fragments are examples of a human intervention while human antibodies are still a natural product because the intervention is only isolation, which does not significantly change or manipulate the naturally occurring product.
The instant claims only require the naturally occurring antibody characteristics, which does not further limit or distinguish the antibodies from those found in nature. The instant claims do not recite any elements in addition to the natural products that impose meaningful limits on the claim scope and would substantially foreclose others from using these natural products.
Therefore, claims 1-6 are not patent eligible.
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.
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, 4, 5, 6-11, and 13-16 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 is directed to antibodies against SARS-CoV-2 spike comprised of HCDR1-3 of SEQ ID NO: 30 or 46 or one or more variants thereof and LCDR1-3 of SEQ ID NO: 32 or 48 of one or more variants thereof. However, the specific six CDRs are not limited to any of the CDR numbering systems, and thus the sequences of the amino acid sequences of the three CDRs that comprise the antigen binding domain are unclear.
Claim 5 is drawn to the antibody “further comprising a coupling moiety connected to a polypeptide”. In lines 5-6, “the polypeptide or the antibody is selectively linked to the coupling moiety by a linker”. Based on the examples of coupling moiety set forth in the claim, “coupling moiety” is interpreted to be the payload. The structure of this antibody-drug conjugate and the relationship between the polypeptide and the payload (e.g., a drug) are unclear. Because the drug can be linked to the antibody via a peptide linker or to the polypeptide via a peptide linker, in the case where the drug is connected to the antibody via a peptide linker, it is not possible to determine where the polypeptide of line 3 is positioned. The disclosure provides no further guidance regarding the structure of this antibody-drug conjugate, and when the claim is read in light of the specification, the scope of the claim is unclear.
Claim 11 recites the limitations "the… polynucleotide, recombinant vector, and host cell of claim 1”. There is insufficient antecedent basis for these limitations in the claim, because claim 1 is only drawn to the antibody, not the polynucleotide, vector, or host cell.
Claims 4, 6-11, and 13-16 also included in this rejection for being dependent on claim 1 and for failing to cure the indefiniteness.
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.
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 1-11 and 13-16 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. This is a written description rejection.
“[T]he purpose of the written description requirement is to ‘ensure that the scope of the right to exclude, as set forth in the claims, does not overreach the scope of the inventor’s contribution to the field of art as described in the patent specification.’” Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1353-54 (Fed. Cir. 2010) (en banc) (quoting Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 920 (Fed. Cir. 2004)). To satisfy the written description requirement, the specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention. Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1562-63, 19 USPQ2d 1111 (Fed. Cir. 1991). See also MPEP 2163.04.
The claims are directed to an antibody or antigen-binding fragment against SARS-CoV-2 spike(S) comprised of amino acid sequences drawn to three heavy chain CDRs and three light chain CDRs. However, the combination of the six specific CDRs necessary to form the antigen binding domain of each antibody is not set forth precisely to indicate which set of heavy chain CDRs are to be paired with which set of light chain CDRs. The claims are broadly drawn to antibodies comprised of various combinations of HCDR1-3 and LCDR1-3 of amino acid sequences with variations within the CDRs.
Further, the antibodies of claim 4 claim are comprised of heavy chain variable region and light chain variable amino acid sequences that are at least 70% identical to SEQ ID NOs: 30, 46 and 32, 48, respectively. By virtue of the percent identity language, this claim encompasses variants that do not require all three CDRs from a particular parental antibody.
Claims 7-11, 13, and 16 are drawn to a method of making the antibody as well as nucleotides, vectors, and host cells. As the antibody of claim 1 is not sufficiently described, neither are these related claims.
Regarding the limitations of claim 5 directed to the antibody linked to a coupling moiety that is at least one of radionuclides, drugs, toxins, cytokines, enzymes, fluoresceins, carrier proteins, lipids, and biotin, there is not sufficient written description support for these vast genera of modifications associated with enormous structural diversity. For example, the moieties drug and lipids are generally disclosed, and no common structural features are identified. The disclosure does not reasonably convey possession of the genus of antibody-lipid or antibody-drug conjugates.
As detailed below, applicant’s disclosure is not sufficient to demonstrate possession of the entire claimed genera, and as such, applicant’s disclosure does not satisfy the written description requirement of 35 U.S.C. 112(a).
Antibodies generally share certain characteristics such as Fc regions or hinge regions. However, these structures are not correlated with the binding function of the antibody. 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 that provide the majority of the contact residues for the binding of the antibody to its target epitope. 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 (see Almagro et al, Section 3 “Antibody Structure and the Antigen Binding Site” and Figure 1; instant PTO-892).
The art recognizes that the CDRs define the binding properties of an antibody and that even single amino acid changes to this region can completely abrogate the binding specificity of an antibody. See for example Kussie (instant PTO-892), who demonstrates that a single amino acid change in the heavy chain of an antibody which binds p-azophenylarsonate (Ars) completely abrogates the ability of the antibody to bind Ars but adds the functionality of binding the structurally related p-azophenylsulfonate (see abstract).
Furthermore, even when provided with several related antibodies that bind the desired target, this does not represent the astronomical and potentially unknowable breadth of all possible amino acid sequences which will result in the desired binding properties. This is exemplified by the Court decision in Abbvie (Abbvie v Janssen 759 F.3d 1285 (Fed. Cir. 2014)), where Abbvie developed over 200 antibodies that shared 99.5% identity in the variable regions (pg 7) and which bound the target, but in no way allowed one to envisage the unique structure of Centocor’s antibodies which bound the same target but shared only 50% sequence similarity (see table on pg 11).
As another example, see Chen et al., 1995 (instant PTO-892), which demonstrates single amino acid changes in the VH CDR2 sequence can increase binding, decrease binding, destroy binding, or have no effect on binding when compared to the wild-type antibody. See also Koenig 2017 (instant PTO-892), which provides a large mutation analysis study where every amino acid in both variable regions are substituted with every other amino acid. Looking at figure 1 of Koenig, the bottom half of each section (labeled VEGF) relates to the ability of the mutant to bind the original target, with blue meaning a reduced affinity and black meaning a complete loss of binding ability. In VH-CDR2, for example, mutating any given residue to cysteine, resulted in reduced binding at 12 residues and a complete loss of binding at 5 residues. That is, at 100% of the positions, mutation to cysteine reduced or ablated the antibody’s ability to bind the target. Looking at a specific position, in 100% of the mutations of residue 55, binding was reduced (15/19) or eliminated (4/19). While residues 56-65 appear more tolerant of change, residues 50-55 are generally intolerant of change.
It is appreciated that Koenig is studying one specific antibody, and there is no evidence that the instant antibodies would react in the same way. However, this is part of the problem. It is entirely unclear from the specification which residues of Applicant’s CDRs are tolerant or intolerant to change, and whether those tolerant positions are only tolerant to conservative mutations. The fact that some residues might tolerate mutation does not convey to the skilled artisan that Applicant knew which of the claimed residues were tolerant of such, i.e. does not convey that Applicant was in possession of those sequences that are mutated yet preserve the claimed function. The specification fails to convey possession of an invention commensurate in scope with what is now claimed and therefore fails to meet the written description requirement.
Looking at Koenig figure 2A, ~200 mutations in the CDR region of the VH chain completely abrogate any binding. While 2B appears to indicate that the CDRs of VL are more tolerant of change than the heavy chain CDRs, still over half of the mutations reduce binding compared to the parent. Thus, making changes to the CDR sequences of an antibody is a highly unpredictable process, and the skilled artisan could not a priori make any predictions regarding such mutations with any reasonable expectation of success nor envisage the breadth of structurally unrelated CDR combinations that would still possess the required functions. Without this guidance or direction, the skilled artisan would not consider applicant to be in possession of the claimed genus of antibodies because the skilled artisan recognizes that even seemingly minor changes made without guidance or direction as to the relationship between the particular amino acid sequence of the instantly claimed antibody and its ability to bind antigen, can dramatically affect antigen-antibody binding.
As specificity of an antibody stems from the interaction of six CDRs, sufficient information must be provided to show that the inventor had possession of the invention as claimed. MPEP §2163(II)(A)(3)(a) also discusses Univ. of Rochester v. G.D. Searle & Co., 358 F.3d 916, 927, 69 USPQ2d 1886, 1894-95 (Fed. Cir. 2004), where a method of using a PGHS-2 inhibitor did not meet the written description as the inhibitor itself was not sufficiently described, clearly indicating that written description of the compound is still required in a method of using that compound. In this case, it is clear from the specification that the invention comprises new antibodies, or at the least disclosure of new antibodies that could not have been envisaged from the prior art, which indicates that the prior art was not in possession of all antibodies against SARS-CoV-2 spike(S) with HCDR1-3 from SEQ ID NO: 30 or 46 variants thereof and LCDR1-3 from SEQ ID NO: 32 and 48 or variants thereof.
Thus, the prior art cannot provide sufficient written description of this genus of compounds and the specification as filed does not sufficiently describe the genus either as there is an unknown amount of structurally distinct antibodies in this genus (see Amgen and Centocor decisions discussed above).
To satisfy the written description requirement, a patent specification must describe the claimed invention in sufficient detail that one skilled in the art can reasonably conclude that the inventor had possession of the claimed invention.
In the instant case, the specification provides insufficient direction or guidance concerning the relationship between the structure of the possible antibody to demonstrate possession of the breadth of the genus of anti-SARS-CoV-2 spike(S) antibodies encompassed by the instant claims, especially in view of the unpredictability of such an endeavor. The prior art, as evidenced by Edwards et al., 2003 (instant PTO-892), teaches there is a substantially huge antibody diversity produced to one single antigen target. Edwards provides evidence that over 1000 antibodies, all different amino acid sequences, were generated towards one single protein antigen target (see abstract). Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function … does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is”).
According to the specification, the applicant has disclosed at least 2 species of antibodies against SARS-CoV-2 spike(S) that comprise specific combinations of the claimed HCDR1-3 and LCDR1-3 amino acid sequences. Although applicant has disclosed two species within said genus antibodies, the specification does not provide adequate written description for the entire claimed genus, because one skilled in the art would be unable to immediately envision, recognize, or distinguish most of the members comprised within the genera claimed, specifically which six CDR amino acids sequences from the recited CDRs should be combined to yield an antigen-binding region that is capable of binding spike(s) protein of SARS-CoV-2.
There is no way to determine if these antibodies represent the full breadth of what is claimed. The disclosure of these specific antibodies would not convey to the artisan that applicant was in possession of the full genus of all antibodies which possess the required functions nor does it allow the skilled artisan to envisage the specific structure of such antibodies.
Applicant has not described the claimed invention sufficiently to show they had possession of the claimed genera of antibodies that bind spike(s) protein of SARS-CoV-2. Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester v. G.D. Searle & Co., 358 F.3d 916, 69 USPQ2d 1886 (Fed. Cir. 2004).
To provide adequate written description and evidence of possession of the claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. In the instant case, the only factors present in the claims are a recitation of one generic, broad genus that encompassed a diverse and huge number of possible antibodies that bind the disclosed epitope. The specification does not provide a consistent structure for all of the possible antibodies and fails to provide a representative number of species for the claimed genus. Accordingly, in the absence of sufficient recitation of distinguishing identifying characteristics, the specification does not provide adequate written description of the claimed genus.
Satisfactory disclosure of a "representative number" depends on whether one of skill in the art would recognize that the applicant was in possession of the necessary common attributes or features of the elements possessed by the members of the genus in view of the species disclosed. For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only two species within the genus.
For claims drawn to a genus, a generic statement that defines a genus of substances by only their functional activity does not provide an adequate written description of the genus. Reagents of the University of California v. Eli Lilly, 43 USPQ2d 1398 (CAFC 1997). The recitation of a functional property alone, which must be shared by the members of the genus, is merely descriptive of what the members of the genus must be capable of doing, not of the substance and structure of the members. The Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties (e.g., high affinity, neutralization activity, competing with a reference antibody for binding), “[c]laiming antibodies with specific properties, e.g., an antibody that binds to human TNF-α with A2 specificity, can result in a claim that does not meet written description even if the human TNF-α protein is disclosed because antibodies with those properties have not been adequately described." Centocor Ortho Biotech Inc. v. Abbott Labs., 97 USPQ2d 1870, 1875, 1877-78 (Fed. Cir. 2011). An antibody described only by functional characteristic, such as antibody that binds spike(S), without any known or disclosed correlation between that function and the structure of the sequence, is not a sufficient identifying characteristic for written description purposes, even when accompanied by a method of obtaining the biomolecule of interest. In re Bell, 991 F.2d 781, 26 U.S.P.Q.2d 1529 (Fed. Cir. 1993). In re Deuel, 51 F.3d 1552, 34 U.S.P.Q.2d 1210 (Fed. Cir. 1995).
With the exception of specifically disclosed antibodies with specific CDRs, the skilled artisan cannot envision the detailed chemical structure of all of the encompassed antibodies, and therefore conception is not achieved until reduction to practice has occurred, regardless of the complexity or simplicity of the method of isolation. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method of isolating it. The product itself is required. See Fiers v. Revel, 25 USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddes v. Baird, 30 USPQ2d 1481 at 1483. In Fiddes, claims directed to mammalian FGF's were found to be unpatentable due to lack of written description for that broad class. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. §112 is severable from its enablement provision (see page 1115).
Therefore, claims 1-11 and 13-16 do not meet the written description requirement.
Conclusion
No claim is allowed.
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Jennifer Benavides
Examiner
Art Unit 1675
/JENNIFER A BENAVIDES/Examiner, Art Unit 1675
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