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 .
Claims 1-28 are examined on the merits. Examination of the claims will largely focus on the species of antibody identified as R200-1B9 and sequences associated with it.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/31/24 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Specification
Objections
Specific deficiency - This application contains sequence disclosures in accordance with the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 - 1.825.
For example, the sequences disclosed in the table presented on pages 25-27 of the specification list amino acid SEQ ID NO:s for several CDR2 sequences that are 3 amino acids in length. According to ST.26 sequence rules, an amino acid sequence shorter than 4 amino acids should not be identified by a SEQ ID NO: and should be present in the Sequence listing. In addition, the SEQ ID NO:s associated with the 3 amino acid long CDR2s are “000” in the sequence listing. For example, SEQ ID NO: 31 is “000”. It is suggested that applicants remove all SEQ ID NO:s in the specification that are associated with 3 amino acid long sequences.
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. See pages 19 and 25 of specification.
Claim Objections
Claims 2-8 are objected to because of the following informalities: claims 2-8 are dependent claims of claim 1 and should begin with the article “The”. Appropriate correction is required.
Claims 9, 10, 12, 16, 18 and 19 are objected to because of the following informalities: claims 9, 10, 12, 16, 18 and 19 should begin with the article “A” or “An”. Appropriate correction is required.
Claims 12 is objected to because of the following informalities: claim 12 recites, “of claim 12 in a containing…”, it is suggested that claim 12 recite, “of claim 12 containing…”. Appropriate correction is required.
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.
Notwithstanding any other provision of law, no patent may issue on a claim directed to or encompassing a human organism.
Claims 18 and 26 are 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). The claims are darwn to host cells, which include human organisms. If claims 18 and 26 are amended to recite “An isolated host cell…”, this rejection can be overcome.
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 1-12, 15 and 20-25 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally-occurring element of nature that is not patent-eligible pursuant to the Supreme Court decision in Association for Molecular Pathology v. Myriad Genetics, Inc., -- U.S. -- (June 13, 2013) (hereafter “Myriad”).
Based upon an analysis with respect to the claims as a whole, claim(s) 1-12, 15 and 20-25 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The claims do not fall within at least one of the four categories of patent eligible subject matter 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 (these claims are interpreted in light of the most recent Guidelines (See “https://www.uspto.gov/patent/laws-and-regulations/examination-policy/subject-matter-eligibility)).
These claims are analyzed for eligibility in accordance with their broadest reasonable interpretation. In view of the Subject Matter Eligibility Test for Products and Processes and the Steps cited below (See flowchart at https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf), the claims are directed to an ineligible product/process as further detailed below.
In this case, claim(s) 1-12, 15 and 20-25 recite or are directed to a composition of matter (Step 1) and recite natural phenomenon(s) (in this case, an antibody and the encoding sequences were isolated from human PBMCs following a natural infection by COVID in said human) that are directed to a judicial exception (in this case, a natural phenomenon)(Step 2A). This process of isolating these antibodies is detailed on pages 36-39 of the specification and summarized in Figure 1
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Thus the claimed product is not markedly different from its naturally occurring counterpart (see Part I.A.3 of the Interim Eligibility Guidance; Example 2, p. 29). Thus the claims also read upon combining the antibody or antigen binding fragment with a pharmaceutically acceptable excipient, or the presence of a container in a kit that also includes the antibody, however, a composition of matter as recited in Step 1 and a natural phenomenon as recited in Step 2A.
The claims thus recite a nature-based product limitation that does not exhibit markedly different characteristics from its naturally occurring counterpart, or is directed to a “product of nature” exception.
Further, in view of Step 2B and the “No” pathway, the claims do not recite additional elements that amount to significantly more than the judicial exception. While the claimed invention also requires a pharmaceutically acceptable excipient to be added with the antibody or a kit comprising a container and the antibody, but not requiring that the container house the antibody, these additional limitations do not amount to significantly more than the judicial exception since the carrier does not provide any additional elements to change a property or function of the antibody.
As pursuant to the Office’s interpretation of the Myriad decision, a recitation of a naturally-occurring nucleic acid, protein, or any natural product of nature that does not have a substantial or marked difference from the natural product is not patent eligible subject matter. Therefore, claims 1-12, 15 and 20-25 as written, read upon a non-naturally occurring antibody that was found to have occurred naturally in nature without being subject to the "hand-of-man" and resulting in a substantial or markedly different product from that found in nature. Therefore, claim(s) 1-12, 15 and 20-25 do not recite eligible subject matter under 35 U.S.C. 101 in view of the Subject Matter Eligibility Test for Products and Processes, and the claimed invention is directed to non-statutory subject matter. This rejection is necessitated by expanded 35 USC §101 USPTO training in view of the USPTO’s interpretation of Myriad. Applicant is directed towards the USPTO memos, which support the analysis of the claims (https://www.uspto.gov/sites/default/files/documents/peg_oct_2019_update.pdf); please review the latest materials regarding 35 USC §101 rejections. It is suggested that applicant cancel the rejected claims, draw the rejected claims to read upon a non-naturally occurring antibody, recite specific steps that are non-routine/non-conventional, and/or recite products/processes which are substantially or markedly different from the judicial exceptions. Applicant is cautioned to amend the claims according to these suggestions utilizing limitations for which the application would have support.
Claim Rejections - 35 USC § 112
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 13, 14, 24, 25, 27 and 28 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 a inhibiting a SARS-CoV-2 infection by administering an effective amount of a monoclonal antibody comprising the CDR, does not reasonably provide enablement for preventing a SARS-CoV-2 infection or COVID-19 in a subject by administering an antibody or antigen binding fragment thereof that comprises heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDRs of SEQ ID NO: 30, GPS and SEQ ID NO: 32 or an antibody or antigen binding fragment thereof comprising SEQ ID NO:s 1 and 2, more specifically R200-1B9. 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 and a kit for preventing a SARS-CoV-2 infection or COVID-19 in a subject by administering an antibody or antigen binding fragment thereof that comprises heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDRs of SEQ ID NO: 30, GPS and SEQ ID NO: 32 or an antibody or antigen binding fragment thereof comprising SEQ ID NO:s 1 and 2, more specifically R200-1B9.
The specification states: As used herein, the terms "prevent," "prevents," or "prevention" and "inhibit," "inhibits," or "inhibition" (and grammatical equivalents thereof) are not meant to imply complete abolition of disease and encompasses any type of prophylactic treatment that reduces the incidence of the condition, delays the onset of the condition, and/or reduces the symptoms associated with the condition after onset. [see page 15]. However, this definition does not specifically mention infection by SARS-CoV-2.
The limitation “for preventing CoV infection” is interpreted to require that the composition can stop a coronavirus infection from occurring once administered to a host.
State of the prior art/Predictability of the art. The state of the art related to coronavirus treatment includes vaccines, such as vaccines for vaccinating against COVID-19. The art teaches that some vaccines are effective at reducing severe illness, but that preventing infection is not realistic. For example, Table 19 presented herein is from the package insert of a SPIKEVAX injectable vaccine by ModernaTX, Inc. This vaccine has proven to be reliable at reducing the severity of COVID-19 infections. This version of the COVID-19 vaccine is a 2025-2026 formula. Table 19 summarized the vaccine efficacy of SPIKEVAX at 93% in all 14, 287 participates tested. However, approximately 9.6 per 1,000 Persons of those receiving the vaccine still contracted COVID-19. Therefore, the SPIKEVAX vaccine has been proven to be effective, but it did not prevent infection in all recipients that received it.
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The claimed method and kit only requires the administration of a single binding agent (the elected antibody having the comprises heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDRs of SEQ ID NO: 30, GPS and SEQ ID NO: 32 or an antibody or antigen binding fragment thereof comprising SEQ ID NO:s 1 and 2, more specifically antibody R200-1B9. 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. Applicants have provided a working example in which SARS-CoV-2 viruses are tested for binding by specific monoclonal antibodies and the ability of these antibodies to inhibit cell infection in an in vitro setting. [see page 41 of specification] However, applicants have not tested an antibody or antigen binding fragment thereof, which comprises the comprises heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDRs of SEQ ID NO: 30, GPS and SEQ ID NO: 32 or an antibody or antigen binding fragment thereof comprising SEQ ID NO:s 1 and 2, more specifically R200-1B9 in the ability to prevent a SARS-CoV-2 infection or COVID-19 in a subject.
Guidance in the specification. The specification provides guidance towards using the antibodies or antigen binding fragments thereof to prevent SARS-CoV-2 infection or COVID-19 in a subject.
Amount of experimentation necessary. Additional research is required in order to determine how effective an antibody or antigen binding fragment thereof, which comprises the heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDRs of SEQ ID NO: 30, GPS and SEQ ID NO: 32 or an antibody or antigen binding fragment thereof comprising SEQ ID NO:s 1 and 2, more specifically R200-1B9 in the ability to prevent a SARS-CoV-2 infection or COVID-19 in a subject.
For the reasons discussed above, it would require undue experimentation for one skilled in the art to use the claimed methods.
Claims 16-18 and 26 are rejected under 35 U.S.C. 112, first paragraph, as containing 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.
Applicant broadly claims a host cell or expression vector or nucleic acid containing the nucleic acids of claims 16-18 and 26. 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 expression vector.
With respect to the unisolated host cells and transgenes as “nucleic acids” or “expression vectors “of the instant claims discussed above, the state of the art at the time of filing was such that one of skill 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 (Wall et Al., Theriogenology, Vol. 45, Pg. 57-68, 1996).
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; e.g., specific promoters, presence or absence of introns, etc. (Houdebine et Al., Journal of Biotechnology, Vol. 34, Pg. 269- 287, 1994). Furthermore, transgenic animals are regarded to have within their cells, cellular mechanisms that prevent expression of the transgene, such as methylation or deletion from the genome (Kappell et Al., Current Opinions in Biotechnology, Vol. 3, Pg. 548-553, 1992). Houdebine (Comparative Immunology, Microbiology, and Infectious Diseases, Vol. 32, Pg. 107-121, 2009) teaches progress has been made in the field of transgenic animals for production of foreign proteins (Abstract); however, constructing an efficient expression vector to produce a therapeutic protein is not a standard operation (Pg. 116, Paragraph, second). Therefore, undue experimentation is required to make and use a transgene and transgenic animal to produce the antibody and antibody fragments of the instant claims.
Examples in the literature aptly demonstrate that even closely related species carrying the same transgene construct can exhibit widely varying phenotypes. Mullins (1993, Hypertension, Vol. 22, No. 4, pp. 630-633) states that not all animals express a transgene sufficiently to provide a model for a disease as the integration of a transgene into different species of animal has been reported to give divergent phenotypes. For example, several animal models of human diseases have relied on transgenic rats when the development of mouse models was not feasible. Mullins (1990, Nature, Vol. 344, 541-544) produced outbred Sprague-Dawley x WKY rats with hypertension caused by expression of a mouse Ren-2 renin transgene. Hammer (1990, Cell, Vol. 63, 1099- 1112) describes spontaneous inflammatory disease in inbred Fischer and Lewis rats expressing human class I major histocompatibility allele HLA-B27 and human 02- microglobulin transgenes. Both investigations were preceded by the failure to develop human disease-like symptoms in transgenic mice expressing the same transgenes that successfully caused the desired symptoms in transgenic rats (Mullins, 1989, EMBO J., Vol. 8, pages 183-191). Thus, the use of nonmurine species for transgenesis will continue to reflect the suitability of a particular species for the specific questions being addressed, bearing in mind that a given construct may react very differently from one species to another.
The examiner notes here, in addition to these issues, even assuming arguendo a person having ordinary skill in the art could make a host organism with functional transgene that encodes the instantly recited SEQ ID NO: 1, there is no predictability that the host will survive its expression. The transgene depends on the host for function and harm to the host, including death, renders the transgene nonfunctional and thus not enabled.
The art is well-aware of side effects caused by expressing proteins, such as therapeutic antibodies. In a transgenic cell or animal that expresses the same, the antibody will exert any possible side effect it can. It is not administered but chronically present and so such side effects are chronic and potentially more serious than any from an administered antibody. Hansel (Nature Reviews Drug Discovery, Vol. 9, Pg. 325-337, 2010) teaches in their table 1 on page 328 numerous exemplary side effects from licensed monoclonal antibodies to include: increased bleeding risk, infection, heart failure, cancer, thyroid disorder, autoimmune reactions, and cytokine release syndrome (CRS) to name only a few. One or more such effects, or similar, may occur with the therapeutic antibody instantly recited when administered and indeed be exacerbated by chronic exposure due to internal expression. The instantly encoded antibody binds a mammalian protein and so may very well target related or unrelated proteins in the transgenic host, leading to such side effects. For all these reasons, previously raised and new, transgenes are not enabled.
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 recite the term "isolated" before the recitation, "host cell" and by amending the vector and polynucleotide claims to specify they are not in a transgenic animal. 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 transgenic animals possessing the claimed host cells, nucleic acid, or expression vector, with a reasonable expectation of success, absent a specific and detailed description in Applicant’s specification of how to effectively practice this and absent working examples providing evidence which is reasonably predictive that the claimed host cell, nucleic acid, or expression vector, commensurate in scope with the claimed invention. The same can be said for the transgenes and transgenic animals encompassed by the instant claims. Thus, the claims are rejected here.
Claims 1 and 4-28 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 a monoclonal antibody or antigen binding fragment thereof that comprises the variable heavy chain of SEQ ID NO: 1 and the variable light chain of SEQ ID NO: 2 or a monoclonal antibody or antigen binding fragment thereof that comprises the heavy chain CDRs of SEQ ID NO:s 27-29 and the light chain CDR of SEQ ID NO:s 30, GPS and SEQ ID NO: 32, or the monoclonal antibody R200-1B9, wherein this monoclonal antibody is directed to SARS-CoV-2, does not reasonably provide enablement for an antibody or antigen binding fragment thereof having a CDR-H1 amino acid sequence of SEQ ID No. 27, a CDR-H2 amino acid sequence of SEQ ID No. 28, a CDR-H3 amino acid sequence of SEQ ID No. 29, a CDR-L1 amino acid sequence of SEQ ID No. 30, a CDR-L2 amino acid sequence of SEQ ID No. 31, a CDR-L3 amino acid sequence of SEQ ID No. 32, wherein the monoclonal antibody is directed to a SARS-related virus or a SARS-CoV-2. 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 the invention commensurate in scope with these claims.
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 claimed invention is drawn an antibody or antigen-binding fragment thereof having a CDR-H1 amino acid sequence of SEQ ID No. 27, a CDR-H2 amino acid sequence of SEQ ID No. 28, a CDR-H3 amino acid sequence of SEQ ID No. 29, a CDR-L1 amino acid sequence of SEQ ID No. 30, a CDR-L2 amino acid sequence of SEQ ID No. 31, a CDR-L3 amino acid sequence of SEQ ID No. 32. The recitation of “having a CDR…amino acid sequence of…” includes fragments of the identified SEQ ID NO: for each CDR. Therefore, the antibody or antigen binding fragment thereof is not strictly defined by the claimed SEQ ID NO:. Furthermore, SEQ ID NO: 31 does not possess an amino acid sequence, rather it is “000” in the sequence listing provided by applicant. Furthermore, figure 3 from Vanshylla et al. (Cell Host and Microbe, 2022, Vol. 30, pages 69-82) reveals that monoclonal antibody R200-1B9 does not exhibit cross reactivity with non-SARS-CoV-2 viruses, like MERS, or SARS-1 or HKU1. Therefore, the enablement of the claimed antibody comprising the identified sequences and its ability to be directed towards a SARS-related virus is not supported based on this information from Vanshylla et al.
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Thus, the claim is are directed to a broad class of antibodies, only defined by its function and amino acid sequences that might be required or might be fragments thereof. However, relative to the claimed openness to fragments of the CDRs, the specification does not give one of ordinary skilled in the art enough information to choose candidate antigen binding structures from the vast number of options that fall within the fragments of the claimed CDRs, and therefore required scientists to engage in a great deal of experimentation and failure. “That is not enablement”—it is a “hunting license.”
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 the antibody or antigen binding fragment having fragments of the claimed CDRs and still be able to inherently bind a SARS-CoV-2, in view of teachings for the specification. 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”. The Federal Circuit concluded that there was a lack of enablement, which was affirmed by the Supreme Court in Amgen.
With regard to the antibody of R200-1B9, the instant specification does not disclose any common structural feature delineating which of the claimed variants of R200-1B9 will have the function of “able to bind the SARS-CoV-2”, 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.
The specification does not reasonably provide enablement to make the invention of claim 1 as it is currently written. The specification does reasonably provide enablement to make and use the invention of R200-1B9 as discussed above.
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 6-8 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.
[escape mutants of SARS-CoV-2 identified as 69-70E, 69-70del, R346S, Q414H, K417E, N439K, N440K, K444Q, V445A, G446V, L452R, Y453F, L455F, G476S, S477N, T478K, E484K, F486V, F490S, Q493R, Q493K, S494P or N501Y]
It is apparent that these escape mutants of SARS-CoV-2 are required to practice the claimed invention because they are a necessary limitation for the success of the invention as stated in the claims. As a required element it must be known and readily available to the public or obtainable by a repeatable method set forth in the specification, or otherwise readily available to the public. If it is not so obtainable or available, the enablement requirements of 35 U.S.C. § 112, first paragraph, may be satisfied by a deposit of these escape mutants. See 37 CFR 1.802. One cannot practice the claimed invention without antibodies that specifically bind to the strain. One cannot determine whether an antibody has the necessary characteristics without access to these escape mutants. Therefore, access to these escape mutants is required to practice the invention. The specification does not provide a repeatable method for testing antibodies for Coronavirus specificity as presently claimed without access to the escape mutants of SARS-CoV-2 and it does not appear to be readily available material.
Deposit of escape mutants of SARS-CoV-2 identified as 69-70E, 69-70del, R346S, Q414H, K417E, N439K, N440K, K444Q, V445A, G446V, L452R, Y453F, L455F, G476S, S477N, T478K, E484K, F486V, F490S, Q493R, Q493K, S494P and N501Y in a recognized deposit facility would satisfy the enablement requirements of 35 U.S.C. 112., because the strains would be readily available to the public to practice the invention claimed, see 37 CFR 1.801- 37 CFR 1.809.
If a deposit is made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made under the terms of the Budapest Treaty and that all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon the granting of a patent, would satisfy the deposit requirements. See 37 CFR 1.808.
If a deposit is not made under the terms of the Budapest Treaty, then an affidavit or declaration by applicants or someone associated with the patent owner who is in a position to make such assurances, or a statement by an attorney of record over his or her signature, stating that the deposit has been made at an acceptable depository and that the following criteria have been met:
(a) during the pendency of this application, access to the invention will be afforded to one determined by the Commissioner to be entitled thereto;
(b) all restrictions imposed by the depositor on the availability to the public of the deposited material will be irrevocably removed upon granting of the patent;
(c) the deposit will be maintained for a term of at least thirty (30) years and at least five (5) years after the most recent request for the furnishing of a sample of the deposited material;
(d) a viability statement in accordance with the provisions of 37 CFR 1.807; and
(e) the deposit will be replaced should it become necessary due to inviability, contamination or loss of capability to function in the manner described in the specification.
In addition the identifying information set forth in 37 CFR 1.809(d) should be added to the specification. See 37 CFR 1.803 - 37 CFR 1.809 for additional explanation of these requirements.
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 1-28 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 1-16, 19-25, 27 and 28 recite the limitation “antibody or antigen-binding fragment thereof”.
This limitation is unclear because "antibody" is defined as: "The term "antibody" is used herein in the broadest sense to refer to molecules with an immunoglobulin like domain (for example IgG, IgM, IgA, IgD or IgE) and includes monoclonal, recombinant, polyclonal, chimeric, human, humanized, multispecific antibodies, including bispecific antibodies, and heteroconjugate antibodies; a single variable domain (e.g., VH, VHH, VL, domain antibody), antigen binding antibody fragments, Fab, F(ab')n, Fv, disulphide linked Fv, single chain Fv, disulphide-linked scFv, diabodies, etc. and modified versions of any ofthe foregoing" [see page 10 of specification] Therefore, the word "antibody" includes monoclonal (mAb) and polyclonal antibodies (pAb) or fragments thereof. Therefore, the claim encompasses polyclonal antibodies with the six CDRs. However, polyclonal antibodies have many and different antibody species. The CDRs or variable regions could be found on one molecule in the pAb or two. The claim can be clarified by the following claim amendments: adding "monoclonal" to the limitation.
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.").
Claims 1-3 are rejected on the basis that it contains 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 different antibodies or antigen binding fragments thereof 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: each antibody or antigen binding fragment possesses a unique variable chain, which results in distinct binding affinities for an epitope, therefore, they possess distinct structures and functions.
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 1 recites, “a CDR-L2 amino acid sequence of SEQ ID NO: 31”, however, SEQ ID NO: 31 does not contain an amino acid sequence. It currently is “000”. This is also the case for SEQ ID NO:s 37, 43, 49, 55, 61, 67, 73, 79, 85, 91, 97 and 103. It is therefore suggested that applicants remove the recitation of these SEQ ID NO:s from claim 1 and replace them with the appropriate amino acid letter sequences, for example, based on the table beginning on page 25, the amino acids GPS represent the CDR2 of the light chain of antibody R200-1B9.
Claims 2-28 are also rejected because they depend from claim 1, but do not remedy this deficiency.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation “R200-1B9”, and the claim also recites “(having a CDR-H1 amino acid sequence of SEQ ID No. 27, a CDR-H2 amino acid sequence of SEQ ID No. 28, a CDR-H3 amino acid sequence of SEQ ID No. 29, a CDR-L1 amino acid sequence of SEQ ID No. 30, a CDR-L2 amino acid sequence of SEQ ID No. 31, a CDR-L3 amino acid sequence of SEQ ID No. 32)” which is the narrower statement of the range/limitation. This broad-narrow recitation also applies to the limitations of antibody R200-2F11, R40-1G8, R568-2G5, R568-2B11, R207-2G4, R40-1C8, R568-2B9, R568-1B3, R568-2E1, R568-1G9, R121-1F1, and R259-1B9. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 2 recites the broad recitation “R200-1B9”, and the claim also recites “(having the variable region heavy chain amino acid sequence of SEQ ID No. 1 and the variable region light chain amino acid sequence of SEQ ID No. 2)” which is the narrower statement of the range/limitation. This broad-narrow recitation also applies to the limitations of antibody R200-2F11, R40-1G8, R568-2G5, R568-2B11, R207-2G4, R40-1C8, R568-2B9, R568-1B3, R568-2E1, R568-1G9, R121-1F1, and R259-1B9. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 1 recites, “having a CDR-H1 amino acid sequence of SEQ ID NO: 27…”. Similar limitations are recited for other amino acid sequences in claim 1. The recitation of “having a” is indefinite because it is unclear if this includes fragments, the CDR of only SEQ ID NO: 27 or a sequence that is larger than SEQ ID NO: 27 since having can be interpreted to be equivalent to comprising (see MPEP 2111.03 IV). Claims 4-28 are also rejected because they depend from claim 1, but do not remedy this deficiency.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 5 recites the broad recitation “at most 0.0025 ug/ml”, and the claim also recites “particularly preferably at most 0.0015 ug.ml” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claims 6-8 recite different amino acid residue mutations which present escape mutants of SARS-CoV-2 viruses, however, the recitation of the mutant amino acid positions are indefinite. For example, the mutant “K417E” (see claims 6 and 8) is unclear where in the spike protein the mutation specifically occurs since no corresponding sequence of a spike protein is also claimed. Furthermore, the spike proteins of SARS-CoV-2 viruses do not possess a singular amino acid length, and therefore it is unclear where in the spike protein the K417E mutation occurs. This also applies to the other escape mutants listed in claims 6-8.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 24 recites the broad recitation “use in the treatment or prevention of a disease caused by SARS-related coronavirus in human subjects”, and the claim also recites “preferably for use in the treatment or prevention of a disease caused by sever acute respiratory syndrome coronavirus 2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 25 recites the broad recitation “use in prevention or treatment of a human subject with SARS-related coronavirus”, and the claim also recites “preferably of infection of a human subject with severe acute respiratory syndrome coronavirus 2” which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Conclusion
No claims are allowed.
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/BENJAMIN P BLUMEL/Primary Examiner, Art Unit 1671
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