DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Election/Restrictions
2. Applicant’s election without traverse of the species of the combination of the rs61330082, rs9770242, and rs59744560 SNPs and the species of pulmonary hypertension in the reply filed on 06 October 2025 is acknowledged.
Claim Status
3. Claims 1, 2, 13, 15-16 and 26-37 are pending and have been examined herein.
Information Disclosure Statement
4. The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered. Claim Amendment
5. Please note that the claim listing provided with the response filed 06 October 2025 appears to have used a different color font (or a light gray font) to identify added and deleted portions of the claims. However, electronically submitted lighter color type is difficult to read. It is requested that Applicant use only black as the type color for claim sets to ensure the legibility of the electronically submitted documents. See MPEP 608.01 “In order to enhance readability of electronic submissions, the USPTO strongly recommends use of a black colored font for text on a white background.”
Specification
6. The continuing information provided at page 1 of the specification under the heading of “Related Application” is not complete and is not consistent with the information provided in the Application Data Sheet (ADS). The specification states “This application claims priority to U.S. Provisional Application No. 63/062,908, filed on August 7, 2020…” However, the present application was not co-pending with the provisional applications since the present application was filed more than a year after the filing of the provisional applications. The specification should be amended to clarify the relationship between the present application and the priority applications. In particular, the first line of the specification should be amended to recite, for example: “This application is the National Stage of International Application PCT/US2021/045005, filed August 6, 2021, filed April 16, 2008, which claims the benefit of U.S. Provisional Application No. 63/062,908, filed on August 7, 2020…”.
Claim Rejections - 35 USC § 101
7. 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, 2, 13, 15-16 and 26-37 are rejected under 35 U.S.C. 101 because the claimed invention is directed to the judicial exception of a law of nature / natural phenomenon, and/or an abstract idea without significantly more. The judicial exception is not integrated into a practical application and the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception for the reasons that follow.
Applicant' s attention is directed to MPEP 2106 “Patent Subject Matter Eligibility” which discusses the Alice/Mayo two-part test for evaluating subject matter eligibility.
Regarding Step 1 of the subject matter eligibility test set forth at MPEP 2106III, the claims are directed to the statutory category of a process.
Regarding Step 2A, prong one, the claims recite the judicial exception of a law of nature. The claims recite the correlation between pulmonary hypertension and the SNPsrs61330082, rs9770242, and rs59744560, as well as the correlation between the SNPs and NAMPT promoter activity (claim 13). As in Mayo Collaborative Services v. Prometheus, the recited relationship is a natural phenomenon that exists apart from any human action. See also Cleveland Clinic Foundation v. True Health Diagnostic, LLC, 2018-1218 (Fed Cir. 2019) which states that “The re-phrasing of the claims does not make them less directed to a natural law.” Note that claim 1 is drawn a method “of identifying a subject having or at risk of developing pulmonary hypertension” and recites only the steps of obtaining a sample from a subject and detecting the presence of a SNP in the sample. Thus, one interpretation of claim 1 is that by detecting the SNPs, the method identifies a subject having or at risk of developing pulmonary hypertension (PH). Further note that claims 15, 16 and 26-37 recite that “the presence of the at least three SNPs indicates that the subject has or is at risk for developing pulmonary hypertension.” Claim 13, which depends from claim 1, and claims 26 and 27 which depend from claim 15, further recite the naturally occurring correlation between the SNPs and NAMPT promoter activity.
The claims also recite the judicial exception of an abstract idea and particularly mental processes.
MPEP 2106.04(a) states that the enumerated groupings of abstract ideas include:
“1) Mathematical concepts – mathematical relationships, mathematical formulas or equations, mathematical calculations (see MPEP § 2106.04(a)(2), subsection I);…
3) Mental processes – concepts performed in the human mind (including an observation, evaluation, judgment, opinion) (see MPEP § 2106.04(a)(2), subsection III).”
Claims 1, 2 and 13 recite “identifying a subject having or at risk of developing pulmonary hypertension.” The claims do not set forth how “identifying” is accomplished and there is no limiting definition in the specification for what is intended to be encompassed by “identifying.” The broadest reasonable interpretation of the “identifying” is that “identifying” may be accomplished by critical thinking processes, such as by reading results from a database or report and mentally drawing the conclusion that a subject has or is at risk of developing PH. Thereby, the “identifying” is an abstract idea.
The claims require performing the step of “assaying” the level of expression of the REST-0003 mediated oligonucleotides. Neither the specification nor the claims set forth a limiting definition for "assaying" and the claims do not set forth how “assaying” is accomplished. The claims do not specifically require performing an active laboratory process in which expression levels are detected. The Free Dictionary (available via URL: <thefreedictionary.com/assaying>, printed on 30 January 2019) defines assaying as including “To evaluate; assess”; or “An analysis or examination.” Accordingly, the broadest reasonable interpretation of the assaying step is that this step may be accomplished by reading information in a database or report to thereby ascertain the level of expression of the oligonucleotides in a sample obtained from a subject. Such “assaying” thereby encompasses processes that may be performed mentally and thus is an abstract idea.
The claims require performing a step of "comparing" methylation levels. Neither the specification nor the claims set forth a limiting definition for "comparing" and the claims do not set forth how comparing is accomplished. The broadest reasonable interpretation of the “comparing” step is that this step may be accomplished by critical thinking processes. Such “comparing” thereby encompasses only an abstract idea / process.
Regarding Step 2A, prong two, having determined that the claims recite a judicial exception, it is then determined whether the claims recite additional elements that integrate the judicial exception into a practical application.
Herein, the claims do not recite additional steps or elements that integrate the recited judicial exceptions into a practical application of the exception(s).
The claims recite the additional steps of obtaining a sample from a subject and detecting the presence of at least three SNPs in the sample. These steps are part of the data gathering process necessary to observe the judicial exception. These steps do not practically apply the judicial exception.
Claims 15, 16, and 26-27 additionally recite a step of “administering an effective amount of a NAMPT inhibitor to the subject having or at risk for developing pulmonary hypertension.
However, this step is conditional and need not occur. At step b), the claims recite detecting the presence or absence of the three SNP, wherein the presence of the three SNPs indicates that the subject has or is at risk of developing PH. Thus, the claims include the possibility that the three SNPs are absent and no administering step occurs.
Additionally, the administering step is not considered to be a practical application because the claims encompass detecting the presence of any allele at the SNPs. Since it has not been disclosed that a nucleotide at the variable position of the SNPs is deleted, presumably all subjects would have a nucleotide at the SNP. Thus, in claims 156, 15 and 28-37, the subjects having any nucleotide at the SNPs would be administered the NAMPT inhibitor since the claims include detecting the presence of any allele at the SNP.
Regarding Step 2B, the next question is whether the remaining elements/steps – i.e., the non-patent-ineligible elements/steps - either in isolation or combination, amount to significantly more than the judicial exception.
Herein, the claims as a whole are not considered to recite any additional steps or elements that amount to significantly more than routine and conventional activity and do not add something “significantly more” so as to render the claims patent-eligible. The additionally recited steps of obtaining a sample from a subject and detecting the presence of at least three SNPs in the sample are recited at a high degree of generality and were well-known, routine and conventional in the prior art. This finding is evidenced by the teachings in the specification. For example, para [0086] of the specification (para numbering herein is with respect to the published application) states: “Nucleic acid samples from a sample taken from a subject can be genotyped to determine the presence and identity of a SNP of interest by methods known to a person of skill in the art.”
See also MPEP 2106.05(d) II which states that:
The courts have recognized the following laboratory techniques as well-understood, routine, conventional activity in the life science arts when they are claimed in a merely generic manner (e.g., at a high level of generality) or as insignificant extra-solution activity.
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
ii. Using polymerase chain reaction to amplify and detect DNA, Genetic Techs. v. Merial LLC, 818 F.3d 1369, 1376, 118 USPQ2d 1541, 1546 (Fed. Cir. 2016); Ariosa Diagnostics, Inc. v. Sequenom, Inc., 788 F.3d 1371, 1377, 115 USPQ2d 1152, 1157 (Fed. Cir. 2015);
iii. Detecting DNA or enzymes in a sample, Sequenom, 788 F.3d at 1377-78, 115 USPQ2d at 1157); Cleveland Clinic Foundation 859 F.3d at 1362, 123 USPQ2d at 1088 (Fed. Cir. 2017);
iv. Immunizing a patient against a disease, Classen Immunotherapies, Inc. v. Biogen IDEC, 659 F.3d 1057, 1063, 100 USPQ2d 1492, 1497 (Fed. Cir. 2011);
v. Analyzing DNA to provide sequence information or detect allelic variants, Genetic Techs., 818 F.3d at 1377; 118 USPQ2d at 1546;
vi. Freezing and thawing cells, Rapid Litig. Mgmt. 827 F.3d at 1051, 119 USPQ2d at 1375;
vii. Amplifying and sequencing nucleic acid sequences, University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 764, 113 USPQ2d 1241, 1247 (Fed. Cir. 2014); and
viii. Hybridizing a gene probe, Ambry Genetics, 774 F.3d at 764, 113 USPQ2d at 1247.
Note that while the claims recite detecting particular SNPS, the identity of the SNP is part of the judicial exception and not something in addition to the recited judicial exceptions. The claims do not require using a particular non-conventional reagent, such as a particular, non-conventional probe or primer consisting of or comprising a specific nucleotide sequence to detect the SNP so as to add something ‘significantly more’ to the recited judicial exceptions.
In Mayo v. Prometheus, the Supreme Court stated: "[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."
This is similar to the present situation wherein the additional steps and elements are recited at a high degree of generality and are all routine, well understood and conventional in the prior art. The recited steps and elements do not provide the inventive concept necessary to render the claims patent eligible. See also Genetic Technologies Ltd. v. Merial L.L.C. 818 F.3d at 1377, 1379 (Fed. Cir. 2016).
For the reasons set forth above, when the claims are considered as a whole, the claims are not considered to recite something significantly more than a judicial exception and thereby are not directed to patent eligible subject matter.
Claim Rejections - 35 USC § 112(b) - Indefiniteness
8. 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 29-37 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 29-31 are indefinite over the recitations of “the anti-NAMPT antibody comprises: CDR1, CDR2, and CDR3 domains of a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 2; and CDR1, CDR2, and a CDR3 domains of a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 3.” It is unclear as to whether the claims intend to define the antibody only in terms of the CDR1, CDR2 and CDR3 regions of the heavy chain and light chain or if the claims intend to define the antibody as comprising a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 2 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 3. In the former instance, it is unclear as whether the claims intend to require 3 copies of SEQ ID NO: 2 and 3 copies of SEQ ID NO: 3 or CDR1, CDR2 and CDR3 which comprise subfragments of any length within SEQ ID NO :2 and 3. Note that the specification does not provide a limiting definition of CDR1, CDR2 and CDR3 as it relates to the language “having an amino acid sequence set forth as.” While the specification provides an example of CDR1, CDR2 and CDR3 sequences present within SEQ ID NO: 2 and 3, the specification does not indicate that CDR1, CDR2 and CDR3 are limited to the sequences underlined in SEQ ID NO: 2 and 3 at Table 2 of the specification. Rather, Table 2 is entitled “Exemplary anti-NAMPT antibodies.”
Similarly, claims 32-37 are indefinite over the recitation of “the anti-NAMPT antibody comprises:CDR1, CDR2, and CDR3 domains of a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 10; and CDR1, CDR2, and a CDR3 domains of a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 11.” .” It is unclear as to whether the claims intend to define the antibody only in terms of the CDR1, CDR2 and CDR3 regions of the heavy chain and light chain or if the claims intend to define the antibody as comprising a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 10 and a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 11. In the former instance, it is unclear as whether the claims intend to require 3 copies of SEQ ID NO: 2 and 3 copies of SEQ ID NO: 3 or CDR1, CDR2 and CDR3 which comprise subfragments of any length within SEQ ID NO :10 and 11.
Claim Rejections - 35 USC § 112(a) – Written Description
9. 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 29-37 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the 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 pre-AIA 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.
For a claim 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 Federal Circuit has cautioned that, for claims reciting a genus of antibodies with particular functional properties, ‘‘[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).
‘‘[A] sufficient description of a genus . . . requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can ‘visualize or recognize’ the members of the genus.” Ariad, 598 F.3d at 1350 (quoting Eli Lilly, 119 F.3d at 1568-69). A ‘‘representative number of species” means that those species that are adequately described are representative of the entire genus. AbbVie Deutschland GMBH v. Janssen Biotech, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus to provide a "representative number” of species. The "structural features common to the members of the genus” needed for one of skill in the art to ‘visualize or recognize’ the members of the genus takes into account the state of the art at the time of the invention. For antibodies, the Federal Circuit has found that possession of a mouse antibody heavy and light chain variable regions provides a structural "stepping stone" to the corresponding chimeric antibody, but not to human antibodies. Centocor, 97 USPQ2d at 1875.
Herein, the claims encompass methods of administering an inhibitor of NAMPT which is an anti-NAMPT antibody to a subject having or at risk of developing pulmonary hypertension.
Regarding anti-NAMPT antibodies, the specification (at para [0073] states “a NAMPT-neutralizing mAb (ALT-100 mAb) reduced multiple indices of NASH severity, suggesting ALT-100 mAb to be a viable and novel approach to address the urgent unmet need to prevent NASH progression/lethality.” The specification also discloses particular anti-NAMPT antibodies in Table 2 which are defined in terms of a specific amino acid sequence.
However, claims 29-31 define the anti-NAMPT antibody as comprising “CDR1, CDR2, and CDR3 domains of a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 2; and CDR1, CDR2, and a CDR3 domains of a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 3.” Claims 32-37 define the anti-NAMPT antibody as comprising”CDR1, CDR2, and CDR3 domains of a heavy chain variable region having an amino acid sequence set forth as SEQ ID NO: 10; and CDR1, CDR2, and a CDR3 domains of a light chain variable region having an amino acid sequence set forth as SEQ ID NO: 11.”
As broadly recited, claims 29-31 encompass anti-NAMPT antibodies comprising a heavy chain that includes CDR1, CDR2 and CDR3 regions that each comprise the full length amino acid sequence of SEQ ID NO: 2 or a heavy chain that includes CDR1, CDR2 and CDR3 regions that comprise any subfragment (i.e., an amino acid sequence of) of SEQ ID NO: 2 and a light chain that comprises CDR1, CDR2 and CDR3 regions that each comprise full length amino acid sequence of SEQ ID NO: 3 or a light chain that includes CDR1, CDR2 and CDR3 regions that comprise any subfragment (i.e., an amino acid sequence of) of SEQ ID NO: 3. Similarly, claims 32-37 as broadly written encompass anti-NAMPT antibodies comprising a heavy chain that includes CDR1, CDR2 and CDR3 regions that each comprise the full length amino acid sequence of SEQ ID NO: 10 or a heavy chain that includes CDR1, CDR2 and CDR3 regions that comprise any subfragment (i.e., an amino acid sequence of) of SEQ ID NO: 10 and a light chain that comprises CDR1, CDR2 and CDR3 regions that each comprise full length amino acid sequence of SEQ ID NO: 11 or a light chain that includes CDR1, CDR2 and CDR3 regions that comprise any subfragment (i.e., an amino acid sequence of) of SEQ ID NO: 11.
However, the specification does not teach a representative number of such anti-NAMPT antibodies. Rather, the specification discloses 3 anti-NAMPT antibodies - i.e., AB1 in which the heavy chain comprises the amino acid sequence of SEQ ID NO: 2 and the light chain comprises the amino acid sequence of SEQ ID: 3; AB2 in which the heavy chain comprises the amino acid sequence of SEQ ID NO: 10 and the light chain comprises the amino acid sequence of SEQ ID: 11; and AB3 in which the heavy chain comprises the amino acid sequence of SEQ ID NO: 23 and the light chain comprises the amino acid sequence of SEQ ID: 3
The specification does not adequately describe the overall structure of anti-NAMPT antibodies in which any one or two or three etc. amino acids within SEQ ID NO: 2 and 3 or with SEQ ID NO: 10 and 11 can be the CDR1, CDR2 or CDR3 region, or in which the full length sequence of SEQ ID NO: 2 or 10 can be each of the CDR1, CDR2 or CDR3 region within the heavy chain variable region or in which the full length sequence of SEQ ID NO: 2 or 10 can be each of the CDR1, CDR2 or CDR3 region within the heavy chain variable region.
A skilled artisan would recognize that the specificity of a conventional antibody is dependent upon six specific CDR sequences and different combinations of CDR sequences greatly alter antigen binding. It is well established in the prior art 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.
The variation encompassed by the presently claimed genus of anti-NAMPT antibodies is large and the specification does not establish that the species described therein is representative of the claimed genus. Thereby, the skilled artisan would not recognize that Applicant was in possession of the invention as broadly claimed at the time the application was filed.
Note that in University of Rochester v G.D. Searle & Co., Inc., Monsanto Company, Pharmacia Corporation, and Pfizer Inc., No. 03-1304, 2004 WL 260813 (Fed. Cir. Feb. 13, 2004), the court held that:
“Regardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to that subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.”
Herein, the disclosure does not show that applicant is in possession of the necessary common attributes or features possessed by the members of the claimed genus of anti-NAMPT antibodies. Accordingly, the skilled artisan would not recognize that applicants were in possession of the invention as broadly claimed at the time the application was filed.
Claim Rejections - 35 USC § 112(a) - Enablement
10. Claims 1, 2, 13, 15, 16 and 26-37 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 methods comprising: a) obtaining a sample from a subject at risk of having or developing pulmonary hypertension and b) detecting the allele present at each of the rs61330082, rs9770242, and rs59744560 SNPs in the sample,
does not reasonably provide enablement for methods of identifying a subject having or at risk of developing pulmonary hypertension (PH) based on the detection of any allele present at each of the rs61330082, rs9770242, and rs59744560 SNPs in a sample obtained from a subject or methods which detect “the presence or absence of at least three SNPs in the sample, wherein the SNPs are rs61330082, rs9770242, and rs59744560 SNPs” and wherein “the presence” of the at least three SNPs indicates that the subject has or is at risk for developing PH. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
The following factors have been considered in formulating this rejection (In re Wands, 858F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988): the breadth of the claims, the nature of the invention, the state of the prior art, the relative skill of those in the art, the predictability or unpredictability of the art, the amount of direction or guidance presented, the presence or absence of working examples of the invention and the quantity of experimentation necessary.
Claims 1, 2 and 13 are drawn to a method for identifying a subject having or at risk of developing pulmonary hypertension (PH) comprising detecting the presence of at least the three SNPs of rs61330082, rs9770242, and rs59744560 SNPs in a sample from a subject Note that each SNP has at least two alternative alleles at the variable / polymorphic position. The prior art teaches that there may be a C or T at rs56133982; a G or a T at rs59744560 and a C, A, G or T at rs9770242. Thus, claims 1, 2 and 13 encompass a method for identifying a subject having or at risk of developing PH by detecting a C or T at rs56133982; a G or a T at rs59744560 and a C, A, G or T at rs9770242 as indicative of the subject having or at risk of developing PH.
Claims 15, 16, and 26-37 are drawn to a method of treating a subject having or at risk of having PH comprising detecting “the presence or absence of at least three SNPs in the sample, wherein the SNPs are rs61330082, rs9770242, and rs59744560 SNPs” and wherein “the presence” of the at least three SNPs indicates that the subject has or is at risk for developing PH. The recitation of detecting the absence of the SNPs implies detecting a deletion of the nucleotide at the variable position. The claims also include detecting a C or T at rs56133982; a G or a T at rs59744560 and a C, A, G or T at rs9770242 as indicative of the subject having or at risk of developing PH
The specification teaches:
[0103] NAMPT promoter SNPs have been identified as indicators that may be used to identify patients having or having an increased risk for an inflammatory condition, such as cardiac ischemia, traumatic brain injury, cancer, chorioamnionitis, nonalcoholic steatohepatitis (NASH), or renal fibrosis.
[0104] NAMPT SNPs were reviewed and refined for assessing risk for inflammatory conditions, with several significantly over-represented in African descent individuals. The SNPs are, rs7789066 (position: chr7:106287306 (GRCh38.p12)), rs116647506 (position: chr7:106287180 (GRCh38.p12)), rs61330082 (position: chr7:106286419 (GRCh38.p12)), rs114382471 (position: chr7:106286288 (GRCh38.p12)), rs9770242 (position: chr7:106285885 (GRCh38.p12)), rs59744560 (position: chr7:106285832 (GRCh38.p12)), rs190893183 (position: chr7:106285663 (GRCh38.p12)), and rs1319501 (position: chr7:106285307 (GRCh38.p12)).
[0105] These NAMPT SNPs contribute to inflammatory condition susceptibility and altering NAMPT promoter activity in response to mechanical stress and to hypoxia with key involvement by hypoxia-induced transcription factor HIF2α significantly influenced by NAMPT promoter SNPs -948T, -1001G, and -2422G, but not by -1535G, known to be a protective SNP in some situations.
Note that the prior art teaches that the rs6133082 SNP occurs at position -1535 (also referred to as -1543) in the NAMPT promoter; rs9770242 occurs at position -1001 of the NAMPT promoter; and rs59744560 SNP occurs at position -948 of the NAMPT promoter
As set forth in para [0105] above, the specification discloses that the T allele at -948 of the NAMPT promoter (rs59744560) and a G allele at -1001 of the NAMPT promoter (rs9770242) are correlated with susceptibility to an inflammatory condition, whereas the G allele at -1525 of the NAMPT promoter (rs61330082) is not correlated with increased susceptibility to an inflammatory condition but is a protective allele “in some situations.” The specification does not specifically teach that the inflammatory condition is pulmonary hypertension and does not specifically teach an association between a particular allele at each of the rs61330082, rs9770242, and rs59744560 SNPs and the occurrence of pulmonary hypertension or risk of developing pulmonary hypertension in subjects.
Regarding pulmonary hypertension, the specification (Example 11 beginning at para [0131]) teaches that the anti-NAMPT monoclonal antibody “ALT-100” was effective at treating a “pre-clinical murine model of chorioamnionitis-induced pulmonary hypertension” (PAH).
Accordingly, the specification does not clearly teach the identity of the alleles at each of the rs61330082, rs9770242, and rs59744560 SNPs whose presence is indicative of a subject having or at risk of developing pulmonary hypertension.
The art of determining an association between SNPs and a phenotype, such as pulmonary hypertension is highly unpredictable. This finding is evidenced by the teachings in the specification which indicate that the G allele at -1525 of the NAMPT promoter (rs61330082) is not correlated with increased susceptibility to an inflammatory condition but rather is a protective allele “in some situations” - which situations are not clearly specified in the present disclosure.
The unpredictability in the art, and particularly in extrapolating the results from one inflammatory disorder to other disorders, is supported by the teachings of Wang et al (Mol. Biol Rep. 2011. 38: 819-825). Wang states (p. 824, col. 1) “this study demonstrates for the first time that the -1535C>T polymorphism correlates with reduced plasma levels of inflammatory markers, including visfatin in CAD patients.” Note that visfatin is also known as NAMPT, that position -1535 is rs61330082 and that reduced levels of visfatin/NAMPT would be correlated with a reduced risk of inflammation. In contrast, the present specification appears to teach that the -1525G (rs61330082) is a protective allele.
Similarly, Bajwa (Critical Care Med. 2007. 35(5): 1290-1295) teaches that while the -1001G (rs9770242) allele is correlated with a grater risk of developing ARDS, patients with the -1543 (rs6130082) T allele had a decreased risk of developing ARDS in patients with septic shock and had better outcomes (e.g., abstract and p. 1292 final col. To p. 1293). Bajwa concludes: “Our results demonstrate an association between the variant T-1001G allele and related haplotype and increased risk of poor outcomes, as well as an apparently protective role for the variant C-1543T allele and related haplotype, in a case-control study of critically ill patients” (p. 1294, col. 1).
Thus the findings of Wang and Bajwa are inconsistent with the teachings n the present specification that the -1535C / rs61330082C allele is a protective allele (para [0105]). Note that the specification (para [0146) relies on Bajwa as teaching the association between NAMPT promoter SNPs and acute respiratory distress syndrome (ARDS): “It has been shown that both plasma NAMPT levels (Bime et al., Am J Respir Crit Care Med (2018), 197:1421-1432) and five NAMPT promoter SNPs predict acute respiratory distress syndrome (ARDS) (Bajwa et al., Crit Care Med (2007), 35:1290-1295) and pulmonary arterial hypertension mortality and are risk factors for severe inflammatory injury.” Note that the Bime (Am J Respir Crit Care Med. 2018. 197(11): 1421 and Online Data Supplement, 10 pages) reference cited by the specification teaches that increased SELPLG expression levels in lung correlated VILI and LPS-induced in mouse models of lung injury (abstract and p. 1427). Bime states “We have previously identified several novel genetic ARDS biomarkers and therapeutic targets, including NAMPT” (p.1422, col. 2). However, Bime does not appear to disclose the presently claimed rs61330082, rs9770242, and rs59744560 SNPs.
Further, a reference co-authored by the present inventor - i.e., Lynn et al (Am. J. Respir Critical Care Med.2020. 201: A4502) teaches that “(t)he haplotype -1535 G /-1001 C has been shown to be a risk haplotype for mortality and higher eNAMPT levels in African Americans with ARDS.” Note again that the specification states that the -1535G (C on complementary strand / rs61330082) is a protective allele “in some situations” but is silent as to the effect of the haplotype of -1535 G /-1001 C on eNAMPT levels and risk of pulmonary hypertension.
The unpredictability in the art is also supported by the teachings of Ye et al (U.S. 20190023809). Ye teaches that haplotypes of NAMPT promoter polymorphisms, rather than individual alleles, were correlated with susceptibility or a protective effect to juvenile idiopathic arthritis. It is reported that the GACT haplotype comprising rs61330082 (G-1535A therein), rs9770242 (A-1001C therein), rs59744560 (C-948A therein) SNPs, and a SNP at -423 of NAMPT was found to be associated with susceptibility to JIA. In contrast, the GCAC haplotype was a significantly protective haplotype; and the GCCC haplotype was associated with severity of JIA.
Undue experimentation would be required to practice the claimed invention because the practioner must first determine which of the alleles at each of rs61330082, rs9770242, and rs59744560 are present together in subjects having pulmonary hypertension and in order to arrive at the claimed method of identifying a subject at risk of having or developing pulmonary hypertension. Given the lack of guidance provided in the specification, including with respect to the identity of an allele present at rs61330082 which is correlated with increased risk of having or developing pulmonary hypertension, the results of such experimentation are unpredictable and thereby undue.
As set forth in Rasmusson v. SmithKline Beecham Co., 75 USPQ2d 1297, 1302 (CAFC 2005), enablement cannot be established unless one skilled in the art "would accept without question" an Applicant's statements regarding an invention, particularly in the absence of evidence regarding the effect of a claimed invention.
Specifically:
"As we have explained, we have required a greater measure of proof, and for good reason. If mere plausibility were the test for enablement under section 112, applicants could obtain patent rights to "inventions consisting of little more than respectable guesses as to the likelihood of their success. When one of the guesses later proved true, the "inventor" would be rewarded the spoils instead of the party who demonstrated that the method actually worked. That scenario is not consistent with the statutory requirement that the inventor enable an invention rather than merely proposing an unproved hypothesis."
Herein, although the level of skill in the art is high, given the lack of disclosure in the specification and in the prior art and the unpredictability of the art, it would require undue experimentation for one of skill in the art to make and use the invention as broadly claimed.
Priority
11. The present claims are entitled to the filing date of International Application PCT/US19US2021/45005, filed 06 August 2021. It is noted that a claim as a whole is assigned an effective filing date rather than the subject matter within a claim being assigned individual effective filing dates. U.S. Applications 63/062,750, 63/063,022 and 63/062,908, each filed 07 August 2020 do not provide support for each of the embodiments in independent the claims, and particularly do not disclose identifying a subject as having or at risk of developing pulmonary hypertension wherein the method comprises detecting each of the rs61330082, rs9770242, and rs59744560 SNPs. For example, while the ‘908 application discloses methods for identifying a subject at risk of having or developing chorioamnionitis comprising detecting each of the rs61330082, rs9770242, and rs59744560 SNPs, teaches that chorioamnionitis can lead to bronchopulmonary dysplasia and that anti-NAMPT antibody was used to treat a murine model of bronchopulmonary dysplasia in mice having induced chorioamnionitis, this application does not detection of pulmonary hypertension per se.
See MPEP 2163 II at “(b) New Claims, Amended Claims, or Claims Asserting Entitlement to the Benefit of an Earlier Priority Date or Filing Date under 35 U.S.C. 119, 120, 365, or 386” states “To comply with the written description requirement of 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph, or to be entitled to an earlier priority date or filing date under 35 U.S.C. 119, 120, 365, or 386, each claim limitation must be expressly, implicitly, or inherently supported in the originally filed disclosure.”
Claim Rejections - 35 USC § 102
12. In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Zhang et al (Cancer Biotherapy and Radiopharmaceuticals. 2018. 33: 460; cited in the IDS).
Zhang teaches a method of assaying a sample obtained from a subject to detect the genotype at each of the rs61330082, rs9770242, and rs59744560 SNPs (e.g., abstract, Table 1, p. 461, col. 2 “Detection of visfatin gene polymorphism”). Note that NAMPT is also known as visfatin. Zhang detected a CC, CT or TT genotype at rs61330082, a GG genotype at rs59744560 and an AA genotype at rs9770242 (p. 462, col. 2). Thereby, Zhang teaches a method comprising: obtaining a sample from a subject; and detecting the presence of at least three SNPs associated with the NAMPT gene in the sample, wherein the SNPs are rs61330082, rs9770242, and rs59744560. Note that the claims recite detecting the presence of the SNP per se and do not require detecting any particular allele at the SNP.
Regarding the recitation that the subject is “at risk of having or developing pulmonary hypertension,” all subjects are considered to be at risk to some degree for developing pulmonary hypertension. The claims do not recite any concrete, material attribute of the subjects that would distinguish the subjects over those in the method of Zhang. Further, Zhang teaches that the subjects include subjects having high visfatin / NAMPT plasma levels (Table 2 and abstract), which is a risk factor for many inflammatory-related diseases (p. 460, col. 2), and thereby would be a risk factor for pulmonary hypertension.
Regarding the preamble of the claim, as set forth in MPEP 2111.02 II: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Herein, the preamble language is a statement of purpose and intended result and does not result in a manipulative difference in the method steps of the claims. Accordingly, the process steps are able to stand alone and the preamble limitation is not considered to materially distinguish the claimed method over the prior art.
Regarding claim 13, since the SNPs that are assayed in the method of Zhang are the same as those required by claim 13, the method of Zhang is also one wherein the SNP is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level. Note again that the claims do not require detecting any particular allele at the SNP and the specification does not define a particular allele at the SNPs which is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level.
13. Claim(s) 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Riordan et al (Circulation. 25 November 2014. Abstract 18879, 130, Suppl 2.)
Riordan teaches a method of assaying a sample obtained from a subject to detect the genotype at each of the rs61330082 (-1535), rs9770242 (-1001), and rs59744560 (-948) SNPs. The reference states “Four NAMPT SNPs (G-1535A,A-1001C, C-948A, T-423C) were genotyped using the Taqman Assay on stroke patient population.” Riordan reports that the ‘protective haplotype’ of GACT was detected in African American subjects who had a significantly lower risk of stroke, whereas carriers of the ‘susceptible haplotype’ of AACT had a 2.16 fold increased risk of stroke.
Thereby, Riordan teaches a method comprising: obtaining a sample from a subject; and detecting the presence of at least three SNPs associated with the NAMPT gene in the sample, wherein the SNPs are rs61330082, rs9770242, and rs59744560.
Regarding the recitation that the subject is “at risk of having or developing pulmonary hypertension,” all subjects are considered to be at risk to some degree for developing pulmonary hypertension. The claims do not recite any specific, material attribute of the subjects that would distinguish the subjects in the claims over those in the method of Riordan.
Regarding the preamble of the claim, as set forth in MPEP 2111.02 II: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Herein, the preamble language is a statement of purpose and intended result and does not result in a manipulative difference in the method steps of the claims. Accordingly, the process steps are able to stand alone and the preamble limitation is not considered to materially distinguish the claimed method over the prior art.
Regarding claim 13, since the SNPs that are assayed in the method of Riordan are the same as those required by claim 13, the method of Riordan is also one wherein the SNP is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level. Further, Riordan detected a G or A (i.e., a C or T on the inverse complement strand) at rs61330082 (-1535); an A or C (i.e., a T or G on the inverse complement strand) at rs9770242 (-1001) and a C or A (i.e., a G or T on the inverse complement strand) at rs59744560 (-948). Note that the claims do not require detecting any particular allele at the SNP and the specification does not define a particular allele at the SNPs which is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level.
14. Claim(s) 1 and 13 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Ye et al (U.S. 20190023809).
Ye teaches a method of assaying a sample obtained from a subject to detect the genotype at each of the rs61330082 (G-1535A therein), rs9770242 (A-1001C therein) and rs59744560 (C-948A therein) SNPs, as well as a SNP at -423 of the NAMPT promoter region (e.g., (para [0206] and [0208]). Ye teaches that the GACT haplotype is associated with susceptibility to juvenile idiopathic arthritis (JIA); the GCAC haplotype is a significantly protective haplotype; and the GCCC haplotype is associated with severity of JIA. Ye (para [0206]) states: “(w)e hypothesize that the susceptible and protective haplotypes are associated with an increase and decrease in NAMPT expression, respectively.”
Thereby, Ye teaches a method comprising: obtaining a sample from a subject; and detecting the presence of at least three SNPs associated with the NAMPT gene in the sample, wherein the SNPs are rs61330082, rs9770242, and rs59744560. Note that the claims recite detecting the presence of the SNP per se and do not require detecting any particular allele at the SNP.
Regarding the recitation that the subject is “at risk of having or developing pulmonary hypertension,” all subjects are considered to be at risk to some degree for developing pulmonary hypertension. The claims do not recite any specific attribute of the subjects in the claimed methods that would distinguish the subjects over those in the method of Ye. Further, Ye teaches detecting haplotypes that are correlated with increased risk and severity of JIA, which haplotypes are associated with increased NAMPT expression. Since increased NAMPT expression is a risk factor for inflammatory diseases (para [0005-0007] and [0213]), those subjects in the method of Ye having the susceptibility haplotypes would be at risk for pulmonary hypertension.
Regarding the preamble of the claim, as set forth in MPEP 2111.02 II: “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction.” Herein, the preamble language is a statement of purpose and intended result and does not result in a manipulative difference in the method steps of the claims. Accordingly, the process steps are able to stand alone and the preamble limitation is not considered to materially distinguish the claimed method over the prior art.
Regarding claim 13, since the SNPs that are assayed in the method of Ye are the same as those required by claim 13, the method of Ye is also one wherein the SNP is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level. Note again that the claims do not require detecting any particular allele at the SNP and the specification does not define a particular allele at the SNPs which is associated with a NAMPT promoter activity level that is higher than a baseline NAMPT promoter level. Further, Ye teaches methods of assaying for NAMPT promoter activity of constructs comprising each of the NAMPT promoter SNPs (Figure 16A; and para [0091] and [0207]).15. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Chen et al. (Circulation. 2017; 135:1532–1546) teaches methods of assaying for plasma extracellular NAMPT (eNAMPT) concentrations in plasma samples obtained from human subjects having pulmonary hypertension (see, e.g., abstract and p.1533, col. 2). Chen found that increased plasma eNAMPT concentrations and lung NAMPT expression were significantly correlated with the occurrence of PAH and with PAH severity (p. 1535, col. 2; p. 1539 final para; and Figure 1). Chen further teaches that inhibition of NAMPT by FK866, a small molecule inhibitor of NAMPT, attenuated symptoms of PAH in a rat model of monocrotaline-induced PH (p. 1538 final para to p. 1539). Chen further states (p. 1542-p. 1543, first para):
“There are several potential mechanisms for the up-regulation of NAMPT in patients with idiopathic PAH and in experimental models of PH. As major mediators contributing to PAH pathobiology, hypoxia, upregulation of growth factors, and inflammatory pathways can also influence NAMPT expression. The NAMPT promoter
has hypoxia-inducible factor–responsive elements that affect the transcriptional regulation of NAMPT.33,34 The factor-1, activating protein-1, and nuclear factor-κB, and TNF-α, interleukin-1β, and interleukin-6 increase NAMPT expression. Epigenetic regulation of NAMPT expression via microRNAs has been demonstrated in PAECs,35
colorectal cancer cell lines, hepatocytes, and TZM-bl HeLa cell lines. It is possible that similar effects could occur in the context of PAH. Further studies in this area are warranted. NAMPT levels are also increased and correlate with disease severity in metabolic syndrome and diabetes mellitus, as well as coronary artery disease. This suggests that NAMPT should be studied as a prognostic biomarker in PAH.”
However, Chen does not teach or suggest methods of treating a subject having or at risk of having pulmonary hypertension comprising: assaying a sample obtained from a subject to detect the presence or absence of an allele at SNPs rs61330082, rs9770242, and rs59744560, wherein the presence of an allele at each of the SNPs is indicative that the subject is at risk of having or developing pulmonary hypertension, and then administering an inhibitor of NAMPT to the subject at risk of having or developing pulmonary hypertension.
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/CARLA J MYERS/Primary Examiner, Art Unit 1682
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