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 .
Election/Restrictions
Applicant’s election without traverse of Group I (claims 22-31) in the reply filed on 6/9/2026 is acknowledged.
Claims 32-48 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected inventions, there being no allowable generic or linking claim.
It is noted that Applicant has not supplied updated claims that contain the appropriate claim status identifiers (e.g. (Withdrawn)). Applicant must supply the appropriate claim identifiers in the reply to this Office Action. See MPEP 714 II (C).
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 5/3/2024, 9/16/2024, and 4/16/2025 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner, except where noted.
The information disclosure statement filed 5/3/2024 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. Specifically, n concise explanation of non-patent literature references 231, 232, and 246 have been provided, and so these references have not been considered.
Nucleotide and/or Amino Acid Sequence Disclosures
Summary of Requirements for Patent Applications Filed On Or After July 1, 2022, That Have Sequence Disclosures
37 CFR 1.831(a) requires that patent applications which contain disclosures of nucleotide and/or amino acid sequences that fall within the definitions of 37 CFR 1.831(b) must contain a “Sequence Listing XML”, as a separate part of the disclosure, which presents the nucleotide and/or amino acid sequences and associated information using the symbols and format in accordance with the requirements of 37 CFR 1.831-1.835. This “Sequence Listing XML” part of the disclosure may be submitted:
1. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 via the USPTO patent electronic filing system (see Section I.1 of the Legal Framework for Patent Electronic System (https://www.uspto.gov/PatentLegalFramework), hereinafter “Legal Framework”) in XML format, together with an incorporation by reference statement of the material in the XML file in a separate paragraph of the specification (an incorporation by reference paragraph) as required by 37 CFR 1.835(a)(2) or 1.835(b)(2) identifying:
a. the name of the XML file
b. the date of creation; and
c. the size of the XML file in bytes; or
2. In accordance with 37 CFR 1.831(a) using the symbols and format requirements of 37 CFR 1.832 through 1.834 on read-only optical disc(s) as permitted by 37 CFR 1.52(e)(1)(ii), labeled according to 37 CFR 1.52(e)(5), with an incorporation by reference statement of the material in the XML format according to 37 CFR 1.52(e)(8) and 37 CFR 1.835(a)(2) or 1.835(b)(2) in a separate paragraph of the specification identifying:
a. the name of the XML file;
b. the date of creation; and
c. the size of the XML file in bytes.
SPECIFIC DEFICIENCIES AND THE REQUIRED RESPONSE TO THIS NOTICE ARE AS FOLLOWS:
Specific deficiency - This application fails to comply with the requirements of 37 CFR 1.831-1.834 because it does not contain a “Sequence Listing XML” as a separate part of the disclosure. A “Sequence Listing XML” is required because the application was filed on 9/25/2023, meaning it is subject to the sequence rules of ST.26, not ST.25. This means an XML file is required, not an ASCII file. It is noted that Applicant has provided an ASCII file for their Sequence Listing.
Required response - Applicant must provide:
• A “Sequence Listing XML” part of the disclosure, as described above in item 1. or 2.; together with
o A statement that indicates the basis for the amendment, with specific references to particular parts of the application as originally filed, as required by 37 CFR 1.835(a)(3);
o A statement that the “Sequence Listing XML” includes no new matter as required by 37 CFR 1.835(a)(4)
AND
• A substitute specification in compliance with 37 CFR 1.52, 1.121(b)(3), and 1.125 inserting the required incorporation by reference paragraph as required by 37 CFR 1.835(a)(2), consisting of:
o A copy of the previously-submitted specification, with deletions shown with strikethrough or brackets and insertions shown with underlining (marked-up version);
o A copy of the amended specification without markings (clean version); and
o A statement that the substitute specification contains no new matter.
Claim Objections
Claim 22 is objected to because of the following informality: it is recommended that in the list of cytokines, the list end with “and/or IL-1α/IL-1F1,” as one or more of the listed cytokines may be used. Appropriate correction is required.
Claim 27 is objected to because of the following informalities: it is recommended that in the list of cytokines, the list end with “and/or IL-1α/IL-1F1,” as one or more of the listed cytokines may be used. Additionally, in line 4 of the measuring step, an extra space appears between “level” and “(s)” that should be removed. Additionally, in line 5 of the measuring step, it is recommended to include “is/are” between “and” and “therefore,” as this phrase still refers to the level(s) of the one or more cytokines recited earlier in the step. Appropriate correction is required.
Claim Interpretation
It is noted that regarding the use of the term “responsive” in the instant claims, para. 36 of the instant specification states, “As used herein, the term "responsiveness" is, unless otherwise specified, synonymous with the term therapeutic susceptibility and is not limited as long as it is a state in which any favorable outcome is consecutively or temporarily obtained due to a treatment of a disease in a subject. Examples of the "favorable outcome" include suppression or improvement of a systemic symptom in a subject, suppression or improvement of pathological symptoms, suppression or improvement of test data reflecting a disease condition, and/or improvement of prognosis of a subject.” This definition will be therefore be used to evaluate how the prior art reads on the “responsive” limitations of the instant claims.
Claim Rejections - 35 USC § 103
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.
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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim 22-31 are rejected under 35 U.S.C. 103 as being unpatentable over Soon et al (Vasculat Medicine, 2010; cited in the Restriction Requirement) in view of Igawa et al. (US 2015/0166666 A1).
Soon teaches the examination of cytokines in conjunction with pulmonary arterial hypertension (PAH; Abstract). Specifically, the expression levels of cytokines IL-4 and IL-1β (along with IL-6) were measured in control and PAH groups (Table 2 and page 921, column 1, “Study Subjects”; instant claims 23 and 28). Samples used were serum samples (page 921, column 1, “Serum Samples and Cytokine Levels”; instant claims 24 and 29). IL-6, IL-4, and IL-1β expression levels were all found to be significantly increased in PAH patients compared to controls. For IL-6 data, based on the expression value determined for a patient, Kaplan-Meier survival analysis was conducted, and could be split into quartiles based on survival data (Figure 2). It is noted that survival analysis was performed for each cytokine that showed to be significantly elevated in PAH patients, though all data is not displayed in Figure 2 (page 923, “Correlations of Cytokine Levels With Survival Time”). Then, for each cytokine examined, survival comparisons were made based on the expression level that led to the greatest difference in survival curve. For IL-6, this value was 9 pg/mL (page 924, columns 1-2, joining para.), and the results are shown for other cytokines in Table 4, where the value for IL-1β was 0.50 pg/mL. IL-6 and IL-1β were also shown to be positively correlated with one another (Table 3).
In their introduction, Soon explains the connection between IL-6 and PAH as it is known in the art (pages 920-921, introduction), which, taken together with the IL-6 data shown in Soon, would consider PAH an IL-6 related disease as claimed. The values for each cytokine that are related to the greatest survival differences can be considered analogous to threshold amounts, and Soon even calls these values cutoffs in their research (page 921, column 2, “Statistics” and page 924, column 2, para. 2).
One of the purposes of the research of Soon is to examine the impact of cytokine expression on survival (see Abstract and page 921, column 1, para. 1), and in the final paragraph of the discussion section on page 926, Soon states, “The strong impact of circulating levels of IL-6, IL-8, and IL-10 on mortality suggests that these cytokines may prove to be important tools in risk stratifying IPAH patients. In this particular cohort, cytokine levels appeared to be more useful than traditional parameters such as hemodynamics and 6MWD. Focused studies to define the temporal changes of these cytokines during disease progression and treatment are now warranted. Finally, the finding that elevated levels of cytokines have an impact on mortality supports the need for further studies to define the potential for targeting these cytokines for therapeutic intervention in PAH.” Thus, the work of Soon is future-focused in using the examined biomarkers to make determinations about PAH disease progression and treatment.
Thus, it would be prima facie obvious that as an avenue for the work suggested by Soon, the survival cutoff values for each significantly elevated cytokine (including IL-1β and IL-4) found by Soon could be used to evaluate a patient’s PAH survival and prognosis. Specifically, the ordinary artisan would recognize that the cutoff values established by Soon could be used as points of comparison for future analysis in order to evaluate survival of a PAH patient, and would thus be analogous to the claimed pre-determined thresholds of instant claim 22. Such testing and analysis is generally the purpose of discovering useful biomarkers, as it allows for patients to be examined with easy and non-invasive sampling methods, and would directly impact the aggressiveness of treatment plans and provide additional information about patient outcomes.
Additionally, the PAH patients of Soon were being treated, but the reference describes that said treatments did not have a large, if any, effect on elevated cytokine levels, and notes that the presence of elevated levels of particular cytokines may indicate advanced disease (page 925, column 2, para. 4). Thus, Soon also indicates that treatments that impact the elevated cytokine levels seen in PAH patients are desired, which indicates these treatments could produce responsive results in PAH patients. Taken with the guidance regarding future analyses described above, it would be prima facie obvious to the ordinary artisan that treatments that impact the elevated cytokines shown by Soon, which are implicated in patient survival, would be desired. In particular, a treatment to target elevated IL-6 levels would be indicated by the teachings of Soon, as this biomarker was already known in the art to be associated with PAH, is significantly elevated in PAH patients, and has clear correlations between its expression and patient survival. The suggestion for the use of such a treatment would also be indicated by the additional biomarkers examined in conjunction with IL-6 by Soon that also showed increased expression in PAH patients, and particularly those markers that showed a positive correlation with IL-6 expression, such as IL-1β.
However, Soon does not clearly teach the use of an IL-6 signaling pathway inhibitor.
Igawa teaches pharmaceutical compositions that are an improvement on existing anti-IL-6 receptor antibodies, and specifically Tocilizumab (Abstract). The reference states that Tocilizumab can be used as a therapeutic agent for IL-6-associated diseases (para. 3). The invention of Igawa specifically alters several regions of Tocilizumab to “enhance the efficacy and improve the pharmacokinetics, so that prolonged therapeutic effect is exerted with a lower frequency of administration, and immunogenicity, safety, and physicochemical properties (stability and homogeneity) are improved. As a result, the present inventors discovered multiple CDR mutations in the variable regions of TOCILIZUMAB that improve the binding ability (affinity) to the antigen,” (para. 43). Their specific antibody includes either SEQ ID NO: 20 or SEQ ID NO: 23 (paras. 55 and 58), which are the same as instant SEQ ID NOs: 1 and 2, respectively, and can also include both sequences together (para. 61). The inventive peptide is specifically indicated for use with IL-6 associated diseases (para. 202).
Prior to the effective filing date of the claimed invention, it would have been prima facie obvious for one of ordinary skill in the art to use the guidance provided by Igawa to use their anti-IL-6 antibody as an IL-6 signaling pathway inhibitor given the teachings and conclusions drawn from Song. Specifically, it would be prima facie obvious that the teachings of Song would motivate the ordinary artisan to use a IL-6 signaling pathway inhibitor, for the reasons described above. Igawa provides such an inhibitor in the form of an antibody, and describes that said inhibitor provides various improvements over an existing IL-6 signaling pathway inhibitor, which would motivate the ordinary artisan to use the antibody of Igawa. There would be a reasonable expectation of success as Igawa teaches that their antibody can be used for IL-6 associated conditions, of which PAH is one (instant claims 22, 25-26, and 30-31).
Regarding claim 27, this claim differs from claim 22 in that rather than pre-determined thresholds, the presence of the measured cytokine is predictive of the level of IL-6 in the subject. As Soon already provides a clear correlation between IL-6 and IL-1β (Table 3), cutoffs for both cytokines are established (Table 4), average levels for both biomarkers in PAH patients were measured and examined (Table 2), and the reference firmly establishes that PAH is an IL-6 associated disease, Soon is considered to render obvious that an elevated IL-1β level in a PAH patient is indicative of an increased IL-6 level in said patient compared to control levels, and the additional data provided by Song can further narrow a predicted range of IL-6 in a PAH patient for a given level of IL-1β (instant claim 27).
Thus, Soon in view of Igawa renders prima facie obvious the methods of claims 22-31.
Conclusion
No claims are currently allowable.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to FRANCESCA F GIAMMONA whose telephone number is (571)270-0595. The examiner can normally be reached M-Th, 7-5pm.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Gary Benzion can be reached at (571) 272-0782. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/FRANCESCA FILIPPA GIAMMONA/Examiner, Art Unit 1681
Prosecution Insights