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
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. This application is a continuation of US Application No. 17/340,196 filed June 7, 2021, which is a continuation of US Application No. 16/301,073 filed November 13, 2018, which is a 371 of PCT/US17/32593 filed May 15, 2017, which claims the benefit of US Provisional Application No. 62/336,017 filed May 13, 2016. All claims have been given an effective filing date of May 13, 2016.
Election/Restriction
Applicant's election without traverse of Group III directed to a method of producing an antibody (Claim 85) in the reply filed on June 30, 2025 is acknowledged. As all claims directed to nonelected subject matter have been cancelled, no claims are withdrawn.
Claim Status
Claim listing filed on June 30, 2025 is pending. Claims 1-84 and 86-104 are canceled. Claim 85 is amended. Claims 105-123 are new. Claims 85 and 105-123 are examined upon their merits.
Information Disclosure Statement
The information disclosure statement filed on 01/14/2022 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because copies of the foreign patent documents and non-patent literature documents are not included in the instant application or the direct parent application (U.S. App. No. 17/340,196). MPEP § 609.02II.B.2 states “if the IDS submitted in the parent application complies with 37 CFR 1.98(a) to (c), copies of the patents, publications, pending U.S. applications, or other information submitted in the parent application need not be resubmitted in the continuing application” [emphasis added]. Because no copies have been included in the instant application or the direct parent application, the references have not been considered. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Specification
The disclosure is objected to because of the following informalities: On page 2, line 11, “in least” should recite “in at least.”
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code. Specifically, there is a hyperlink on page 10, line 25. 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.
Appropriate correction is required. Applicant is urged to carefully review the specification for additional informalities.
Claim Objections
Claim 119 is objected to because of the following informalities: Claim 119 references Table 1. Where possible, claims are to be complete in themselves. Incorporation by reference to a specific figure or table "is permitted only in exceptional circumstances where there is no practical way to define the invention in words and where it is more concise to incorporate by reference than duplicating a drawing or table into the claim. Incorporation by reference is a necessity doctrine, not for applicant’s convenience" (see MPEP § 2173.05(s)). Therefore, instead of referencing Table 1, the mutation sets should be listed in the claim.
Appropriate correction is required.
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.
Claims 109-119 and 123 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 109 recites “VH4 genes or transcripts.” The abbreviation “VH4” needs to be defined in the claims at first use. For the purpose of compact prosecution, “VH4” is interpreted as “variable heavy chain family 4.”
Claims 110 and 112-117 recite specific codon positions (31B, 32, 40, 56, 57, 60, 81, and 89), but no reference sequence is defined in the claims. Given the variations of published sequences contained in databases, it is unclear which positions are encompassed by the claims. For example, Claim 117 recites “with the germline amino acid at codons 31B, 40, and 89,” but without a reference sequence, it is unknown what amino acids are encoded by these codons. Accordingly, recitation of a codon number without reference to a specific sequence is indefinite, and the metes and bounds of the claims cannot be determined. Claims 111 and 118-119 are rejected for their dependence on Claim 110.
Claims 110, 112-114, 117, and 123 recite the limitation "the germline sequence.” There is insufficient antecedent basis for this limitation in the claim. Further, no germline sequence is defined in the speciation. Claims 111, 115-116, and 119 are rejected for their dependence on Claim 110.
Claim 118 recites the limitation “the VH4 germline.” There is insufficient antecedent basis for this limitation in the claim. Further, no VH4 germline sequence is defined in the speciation, and it is unclear what sequences are encompassed by “4-04, 4-28, 4-30, 4-31, 4- 34, 4-39, 4-59, 4-61 or 4-B.”
Claims 111-117 recite the limitation "the VH4 antibody.” There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, “the VH4 antibody” will be interpreted as a VH4 antibody encoded by the “VH4 genes or transcripts” defined in Claim 109, but appropriate correction is required.
Claims 119 recites the limitation "the antibody.” There is insufficient antecedent basis for this limitation in the claim. For the purpose of compact prosecution, “the antibody” will be interpreted as an antibody encoded by the “VH4 genes or transcripts” defined in Claim 109, but appropriate correction is required.
Claim 119 recites “wherein the antibody has a set of mutations selected from Table 1.” Table 1 does not exist in the specification or the drawings. Therefore, it is unclear what is encompassed by “a set of mutations selected from Table 1.” Claim 119 is rejected for indefiniteness.
Claim 123 recites “wherein nucleotide sequences” and it is unclear to what nucleotide sequences are being referred. For the purpose of compact prosecution, “wherein nucleotide sequences” is interpreted as “wherein the nucleotide sequences” in reference to the nucleotide sequences defined in Claim 85.
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 85 and 105-123 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/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. Specifically, the instant claims encompass both natural phenomena and abstract ideas.
Claim 85 is directed to a method for producing an antibody comprising providing a first population of B cells from a subject displaying an immune response against an autoimmune disease and a second population of B cells that do not display said immune response, determining nucleotide sequences for a plurality of immunoglobulin-encoding genes, identifying one or more nucleotide sequences that correspond to an autoimmune response, and producing recombinant antibodies encoded by the nucleotide sequences. Claim 85 specifically recites “subjects displaying an immune response against an autoimmune disease” but because autoimmune diseases do not comprise foreign pathogens, it is understood that the immune response of interest is the autoimmune response itself. “Nucleotide sequences that correspond to the immune response” are not specifically defined in the specification and are interpreted as nucleotide sequences that are present in the first population of B cells and not present in the second population of B cells. The specification defines that methods for producing recombinant antibodies encompass those known in the art (page 16, lines 3-15). Claim 123 recites wherein the nucleotide sequences are evaluated based on heavy or light chain gene families, V-D-J usage, and mutations within the heavy and/or light chains. Because the specification does not specifically define “evaluate,” it is interpreted that “evaluating” the nucleotide sequences is equivalent to observing the nucleotide sequences.
The claims recite a method of making an antibody by the mental/abstract processes of “determining”, “identifying”, and “evaluating” nucleotide sequences. The claims are also directed to the natural phenomena of naturally occurring antibodies that are correlated with autoimmune disease. These judicial exceptions are not integrated into a practical application because the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception. Nothing beyond use of routine and conventional methods are encompassed by the claims in addition to the judicial exceptions.
Therefore, claims 85 and 105-123 do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions.
The rationale for this determination is explained below:
The unpatentability of laws of nature/natural phenomenon was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., 101 USPQ2d 1961 (March 20, 2012), and Association for Molecular Pathology v. Myriad Genetics, Inc. 106 USPQ2d 1972 (2013).
Accordingly, the issues are:
a) the current invention is essentially directed to a method of observing production of a natural law/natural phenomenon (i.e., antibodies involved in autoimmunity; which also constitutes a natural law/natural phenomenon within itself), where the abstract/mental concepts of “determining”, “identifying”, and “evaluating” naturally occurring nucleotide sequences that produce naturally occurring antibodies are observed, and therefore, do not overcome Prong One (Step 2A- Prong One),
b) the current claims fail to recite a practical application of additional elements that integrate the judicial exception into a practical application. The current claims encompass “identifying” naturally occurring immunoglobulin-encoding nucleotides that are correlated with autoimmune diseases and recombinantly producing the naturally occurring antibodies. The claims, for example, are not directed to using the judicial exceptions to affect a particular treatment as discussed in MPEP § 2106.04(d)(2). (Step 2A- Prong Two),
c) nothing significantly more than the judicial exceptions is recited within the claims. The courts have defined that simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to a judicial exception is not “significantly more” (MPEP § 2106.05.I.A). The courts have recognized using polymerase chain reaction to amplify and detect DNA, detecting DNA in a sample, analyzing DNA to provide sequence information, amplifying and sequencing nucleic acid sequences, and determining the level of a biomarker as routine activities in the life sciences when claimed at a high level of generality (MPEP § 2106.05(d).II). Ahmad et al. Clin Dev Immunol. 2012 further teaches that recombinant antibody technology, specifically formulating antibody fragments such as scFv, was a routine laboratory technique before the effective filing date of the instant invention (section 2). (Step 2B).
In Mayo Collaborative Services it was held that:
"Phenomena of nature, though just discovered, mental processes, and abstract intellectual concepts are not patentable, as they are the basic tools of scientific and technological work." Gottschalk v. Benson, 409 U. S. 63, 67 (1972). And monopolization of those tools through the grant of a patent might tend to impede innovation more than it would tend to promote it. [emphasis added].
The Court has made clear that to transform an unpatentable law of nature into a patent-eligible application of such a law, one must do more than simply observe and restate a law of nature while adding the words "apply it." As set forth in the decision,
"[i]f a law of nature is not patentable, then neither is a process reciting a law of nature, unless that process has additional features that provide practical assurance that the process is more than a drafting effort designed to monopolize the law of nature itself," further, "[t]o put the matter more succinctly, the claims inform a relevant audience about certain laws of nature; any additional steps consist of well understood, routine, conventional activity already engaged in by the scientific community; and those steps, when viewed as a whole, add nothing significant beyond the sum of their parts taken separately. [emphasis added]"
The discovery of a naturally occurring correlation between nucleotide sequences of a patient’s antibody repertoire and an autoimmune disease is merely the observation of a law of nature in subjects displaying an autoimmune disease. Accordingly, the current claims simply rely on the recognition of a natural relationship between a patient’s antibody repertoire and antibodies that are involved in autoimmune disease, which are natural phenomena/ processes/ disease states by themselves.
In summary, merely observing and determining the “antibody repertoire of a patient by amplification and sequencing of antibody genes” as described on page 5, lines 8-10 of the specification encompasses the abstract concepts of evaluating, determining, and identifying naturally occurring products. Expressing the observed naturally occurring nucleotides as recombinant antibodies utilizes routine and conventional laboratory techniques that do not result in significantly more than the judicial exceptions.
For these reasons claims 85 and 105-123 are rejected under section 101 as being directed to non-statutory subject matter.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
Claims 85, 105-120, and 123 are rejected under 35 U.S.C. 103 as being unpatentable over Cameron et al. J Neuroimmunol. 2009, and further in view of Tan et al. Arthritis Rheumatol. 2014 as evidenced by Heo et al. Explor Immunol. 2024.
The instant claims are directed to a method for producing an antibody comprising providing a first population of B cells from a subject displaying an autoimmune disease and a second population of B cells that do not display said immune response, determining nucleotide sequences for a plurality of immunoglobulin-encoding genes, identifying one or more nucleotide sequences that correspond to the autoimmune response, and producing recombinant antibodies encoded by the nucleotide sequences that correspond the autoimmune response (Claims 85 and 123). Depending claims recite: wherein the B cells displaying an autoimmune response are from a patient having multiple sclerosis (MS) or rheumatoid arthritis (RA) (Claims 105-106 and 120); the disease is characterized by type II or type III hypersensitivity (Claim 107); the disease is a demyelinating disease (Claim 108); and the immunoglobulin-encoding genes are VH4 genes (Claim 109). Claims 110-119 recite inherent properties of the observed antibodies (mutations, binding affinities, germline sequences) that do not alter the methodological steps outlined in Claim 85 comprising identifying naturally occurring nucleotide sequences and producing recombinant antibodies thereof. Therefore, Claims 110-119 are directed towards the expected results of performing the methodological steps of Claim 85, and art that obviates the methodological steps of Claim 85 inherently obviates the resulting antibodies (MPEP § 2112). Note, “the autoimmune disease” in Claim 120 is interpreted to be synonymous with “the antibody-mediated autoimmune disease” of Claim 108.
Cameron teaches a method comprising sequencing VH4 antibody genes of MS patients and comparing them to VH4 antibody genes of healthy control patients wherein the samples were taken from B cells (page 2, paragraph 2). The analysis revealed a unique pattern of antibody gene replacement mutations in B cells from MS patients that were not prevalent in antibody gene repertoires from B cells of healthy patients (page 2, paragraph 2). Cameron further teaches that MS is a demyelinating disease (page 2, paragraph 2).
Cameron fails to teach wherein recombinant antibodies were produced from the nucleotide sequences that correspond to the immune response (Claim 85) or wherein the autoimmune disease is characterized by type II or type III hypersensitivity (Claim 107).
Tan teaches a method of producing an antibody comprising sequencing the antibody repertoire expressed by B cells of RA patients (abstract and page 2707, paragraph 4) and selecting key antibody sequences for cloning, expression, and characterization to determine their binding and functional properties (page 2707, paragraph 4 and page 2710, paragraph 1). Heo defines that RA is characterized by type II and type III hypersensitivity (abstract).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to take the nucleotide sequences encoding antibodies from the method of Cameron and use them to produce recombinant antibodies as taught in the method of Tan. Both Cameron and Tan teach sequencing the antibody repertoires expressed by B cells from patients with autoimmune diseases (MS and RA respectively). Tan teaches one further step comprising producing recombinant antibodies encoded by the resulting nucleotide sequences in order to study the functional characteristics of the RA-associated antibodies. It would be obvious to perform the method of Cameron and include the further step of producing recombinant antibodies from the nucleotide sequences in order to evaluate the functional characteristics of the MS-associated antibodies. Understanding the functional characteristics of MS-associated antibodies is important to better understand MS disease pathology and inform treatment options. One of ordinary skill in the art would have recognized that the results of combining the methodological steps were predictable.
Claims 121-122 are rejected under 35 U.S.C. 103 as being unpatentable over Cameron et al. J Neuroimmunol. 2009 in view of Tan et al. Arthritis Rheumatol. 2014 as evidenced by Heo et al. Explor Immunol. 2024 as applied to Claims 85, 105-120, and 123 above, and further in view of Ahmad et al. Clin Dev Immunol. 2012.
The teachings of Cameron in view of Tan as they apply to Claims 85, 105-120, and 123 are outlined in the rejection above. Cameron and Tan fail to teach wherein the produced antibody lacks an Fc (Claim 121) and is a single chain variable fragment (scFv) (Claim 122).
Ahmad teaches that producing recombinant antibodies is a routine laboratory technique, specifically producing scFv antibodies that comprise a variable heavy chain and a variable light chain joined together with a short flexible peptide linker or disulfide bond (section 2). In comparison to the parental antibody, these “minimized” antibodies have several advantages including more rapid blood clearance, lower retention times in nontarget tissue, and reduced immunogenicity (section 2).
Based on these teachings, it would have been prima facie obvious to one of ordinary skill in the art, at the time the invention was made, to produce the recombinant antibodies as taught by Cameron and Tan to be scFv “minimized” antibodies that lack an Fc domain as taught by Ahmad. Ahmad teaches that recombinantly producing scFv antibodies is a routine and conventional laboratory technique reviewed by a number of researchers (section 2). Ahmad further teaches that the motivation to produce antibodies in scFv format is because they have advantageous clearance rates and reduced immunogenicity which would be beneficial when studying the MS-associated antibodies in vivo.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARAH COOPER PATTERSON whose telephone number is (703)756-1991. The examiner can normally be reached Monday - Friday 8:00am - 5:00pm EST.
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/SARAH COOPER PATTERSON/Examiner, Art Unit 1675
/JEFFREY STUCKER/Supervisory Patent Examiner, Art Unit 1675