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 .
DETAILED ACTION
Applicant’s amendment filed on 15 January 2026 has been received and entered. Claim 127 is amended. Claims 127-133 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 15 January 2026 is being considered by the examiner.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
(Maintained) Claims 127-130 and 132-133 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 claims contain subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter claimed. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art. See MPEP §2163.
Claim 127 recites that the HRS polypeptide in the administered therapeutic composition comprises an amino acid sequence that is at least 95% identical to SEQ ID NO: 156. Claim 130 further limits the HRS polypeptide to comprise an amino acid sequence that is at least 98% identical to SEQ ID NO: 156, and claim 132 further limits the HRS polypeptide to comprise or consist of an amino acid sequence set forth in SEQ ID NO: 156. Claims 128-129 and 132-133 do not further limit the HRS polypeptide, and so share the same written description issues of their parent claims as discussed below.
The broadest reasonable interpretation of the claimed HRS polypeptide is any HRS polypeptide comprising any amino acid sequence that is at least 95%, 98%, or 100% identical to SEQ ID NO: 156. The breadth of the claimed genus of HRS polypeptides also includes HRS polypeptides that have various substitutions, deletions, and/or additions anywhere within the amino acid sequence, so long as the HRS polypeptide’s amino acid sequence is at least 95% or 98% identical to SEQ ID NO: 156. However, this BRI of the claimed genus of HRS polypeptides is substantially larger than the HRS polypeptides that are supported by the written description in the instant specification and have been disclosed in the prior art.
Turning to the specification, there is no clear and explicit special definition for the claim term “HRS polypeptide” such that there is no limit or description on the required structure of the claimed HRS polypeptide to be useful in the present invention. There is no indication in the specification as to what functional, structural, conformational, and/or sequence differences can be tolerated when one of ordinary skill in the art uses any given HRS polypeptide comprising an amino acid sequence that is at least 95% or 98% identical to SEQ ID NO: 156. The disclosure does not provide sufficient direction such that one of ordinary skill in the art can visualize which species of the large genus of HRS polypeptides would be useful in the instant invention such to convey that Applicant had sufficient possession of the entire genus of HRS polypeptides comprising an amino acid sequence at least 95% or 98% identical to SEQ ID NO: 156.
However, the instant disclosure only provides written description support for the use of a HRS polypeptide comprising an amino acid sequence that is 100% identical to SEQ ID NO: 156 (also referred to as Fc-HRS(2-60)) in the instant methods. Working examples 10-16 demonstrate the usefulness of the specific HRS sequence SEQ ID NO: 156 in experiments applicable to the instant methods. However, adequate description of one HRS protein of a specific sequence is insufficient to be a representative number of species for the entire genus of HRS polypeptides as claimed because the genus is so broad as to include any HRS polypeptide comprising any amino acid sequence that is not 100% identical to SEQ ID NO: 156, including those amino acid sequences various substitutions, deletions, and/or additions. The disclosure does not provide sufficient guidance such that one of ordinary skill in the art can visualize which species of the broad genus of HRS polypeptides would exhibit the functional, structural, conformational, and/or sequence requirements to be therapeutic for treating a neuropilin-2 associated inflammatory lung disease. There is no indication as to what sequence changes could be tolerated such that any HRS polypeptide with an amino acid sequence less than 100% identical to SEQ ID NO: 156 (Fc-HRS(2-60)) conserve the enzyme activity and retain the functional activity of treating NRP2 associated inflammatory lung disease in subject in need thereof.
Therefore, the present disclosure does not provide sufficient written description for the entirety of the claimed genus of HRS polypeptides recited in instant claims 127-130 and 132-133 which reasonably conveys to one of ordinary skill in the art that Applicant had possession of the entire claimed genus of HRS polypeptides.
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.
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.
(Maintained) Claims 127-133 remain rejected under 35 U.S.C. 103 as being unpatentable over Mendlein et al. (US 11,767,520 B2, published 26 September 2023, effectively filed 20 April 2017) in view of Immormino et al. (Neuropilin-2 regulates airway inflammatory responses to inhaled lipopolysaccharide, Am J Physiol Lung Cell Mol Physiol 315: L202–L211, April 2018).
Regarding claims 127, 130 and 131, Mendlein teaches a method of treating inflammatory lung disease, including interstitial lung disease (ILDs), comprising administering a HRS polypeptide comprising a sequence that is 100% identical to instant SEQ ID NO: 156 (Mendlein SEQ ID NO: 157 see sequence search results in IFW), and that the administration improves one or more clinical symptoms of lung inflammation (Mendlein abstract and claims 1, 7, and 8).
Regarding claims 128-129 and 132-133, Mendlein specifically teaches that the lung inflammation is interstitial lung disease (ILD), idiopathic pulmonary fibrosis, systemic sclerosis, asthma, hypersensitivity pneumonitis, and more (Mendlein claims 10 and 12), and that the ILD disease includes sarcoidosis, and since ILD is a lung disease, it is reasonable to interpret that the sarcoidosis is pulmonary (Mendlein claim 12 and col. 6 lns. 29-31).
However, Mendlein does not teach that the inflammatory lung diseases are associated with NRP2, a step of determining NRP2a and/or NRP2b levels in a subject, or that their composition is administered to the subject when the subject has increased levels of NRP2a and/or NRP2b relative to a healthy control.
Immormino teaches a method of determining levels of NRP2 in murine and human samples by using quantitative PCR methods, such as PerfeCTa SYBR Green PCR with a 7300 Real-time PCT system (Immormino pgs. 203-204 bridging para.).
Immormino teaches that NRP2 mRNA expression is dramatically upregulated in lipopolysaccharide(LPS)-induced lung inflammation murine models and greatly increased in ex vivo LPS-induced inflammation of human alveolar macrophages as compared to a healthy control group, therefore indicating that a subject with lung inflammation has increased levels of NRP2 relative to a healthy control group (Immormino Abstract and Fig. 1). Immormino teaches that NRP2 is an important regulator of immune responses in inflammatory lung diseases (Immormino pgs. 208-209 bridging para., and pg. 209 right col. para. 2). Therefore, Immormino discloses that increased levels of NRP2 expression is closely associated with inflammatory lung disease.
It would have been prima facie obvious to one of ordinary skill in the art prior to the effective filing date of the present invention to modify Mendlein’s method by adding the step of determining NRP2 levels in a sample from a subject, compare the NRP2 levels with those from a healthy control, and then use the determined levels of NRP2 in the sample as a biomarker of inflammatory lung disease so that one of ordinary skill in the art could more accurately detect and treat NRP2-associated inflammatory lung disease in a subject with increased NRP2 levels by practicing Mendlein’s method.
One of ordinary skill in the art would have been motivated to determine the levels of NRP2 in a sample from a subject, compare the sample’s NRP2 levels to the NRP2 levels of a healthy control, and use those levels of NRP2 in the sample from the subject as a biological marker for NRP2-associated inflammatory lung diseases with a reasonable expectation of success because Immormino discloses that increased levels of NRP2 expression is closely associated with inflammatory lung disease, thus one of ordinary skill in the art would predictably expect that high levels of NRP2 in a sample from a subject as compared to the NRP2 levels of a healthy control is indicative of lung inflammation, making a sample’s NRP2 levels a useful biological marker of inflammatory lung disease. By using this approach, one of ordinary skill in the art would have a more targeted approach of applying Mendlein’s method of treating inflammatory lung diseases.
Response to Arguments
Applicant's arguments filed 15 January 2026 have been fully considered but they are not persuasive.
Regarding Applicant’s arguments regarding the written description requirement that one of ordinary skill in the art would have the necessary guidance and in silico tools necessary to reasonably predict which HRS sequences are able to maintain their biological function, and what minor mutations can be allowed to maintain functionality with a high degree of accuracy, and to use those tools to avoid deleterious mutations, thus the instant specification and state of the art reasonably support the genus of claimed HRS polypeptides (Remarks pgs. 4-7), there is no indication as to what sequence changes can be tolerated such that the administered HRS would retain its therapeutic activity of treating NRP2 associated inflammatory lung disease in a subject in need thereof. Although there exists plenty of tools and guidance in the art which would assist one of ordinary skill in the art in predicting the structural outcome of a given amino acid mutation in HRS and how that relates to the protein’s normal function, there is no guidance in the art which reasonably conveys what sequence changes can be tolerated to allow the HRS to retain its therapeutic activity in treating NRP2 associated inflammatory lung diseases.
The normal and well understood function of an HRS protein is to attach histidine to its corresponding tRNA, which is essential for incorporation of histidine into proteins during protein synthesis, as evidenced by the abstract of Freist et al. (Histidyl-tRNA Synthetase, Biol. Chem., Vol. 380, pp. 623 – 646, June 1999). There is no evidence in the art that this normal function is related to the therapeutic effect as claimed. In fact, the instant specification indicates that the therapeutic activity of the claimed HRS is due to the HRS binding directly to NRP2, thereby competing with and blocking clinically-relevant NRP2/ligand interactions (Examples 1-3). There is no guidance or evidence in the disclosure or the prior art which points to what structural characteristics are required to be maintained to allow HRS to retain its therapeutic function, nor what types of sequence mutations and/or their locations can be tolerated such that the HRS can retain this therapeutic function. There is also no guidance or evidence relating HRS’s structural characteristics associated with its normal and well understood histidine attachment function to the structural characteristics associated with directly binding NRP2 to provide the therapeutic effect.
Although one of ordinary skill in the art is able to use the guidance and tools available to them to predict the folding and stability characteristics of the HRS’s amino acid sequence and how that relates to its established function of attaching histidine to its corresponding tRNA as understood in the art, this does not necessarily mean that those tools are able to adequately describe all of the therapeutically effective sequences of HRS as it relates to the treatment of NRP2 associated inflammatory lung diseases. Therefore, the present disclosure does not provide sufficient written description for the entirety of the claimed genus of HRS polypeptides recited in instant claims 127-130 and 132-133 which reasonably conveys to one of ordinary skill in the art that Applicant had possession of the entire claimed genus of HRS polypeptides.
Regarding Applicant’s arguments that the instant claims related to the unexpected discovery of a direct binding and functional interaction between HRS and NRP2, and that the combination of references does not teach or suggest such an interaction between HRS and NRP2, and without such a teaching there is no rational or technical reason to actively select patients for optimal treatment based on the patient having increased levels of NRP2 (Remarks pg. 8), Applicant’s argued unexpected discovery is not a claimed feature. The applied art teaches the same steps of the instant method, determining levels of NRP2 a/b in a sample from the subject, and administering a composition comprising a HRS polypeptide to treat a NRP2 associated inflammatory lung disease.
Regarding Applicant’s arguments that one of ordinary skill in the art would not select a biomarker based on its association with a given disease, but rather based on how it is connected to the mechanism of action of the therapeutic agent, allowing for a measurable response to a specific therapeutic intervention (Remarks pgs. 8-9 bridging para.), it is true that a skilled clinician may select biomarkers connected to a therapeutic agent's mechanism of action in order to have some measurable indicator of success of the disease treatment. However, it is also true that indicators of a disease, in this case high NRP2 levels, are useful for selectively diagnosing patients afflicted with said disease. This allows and/or assists one of ordinary skill in the art to accurately identify patients with the lung diseases, and respond with an effective treatment strategy, such as the one taught by Mendlein.
The disconnect between Applicant's argument and the rejection's rationale seems to lie in the understanding of what a biomarker is and/or their role in disease treatment. Applicant argues that a skilled clinician selects a biomarker connected to the mechanism of action of the treatment, thereby providing an optimal measure of response to a specific therapeutic intervention. This approach is useful, for example, for monitoring the success of a treatment regimen. The rejection contends that the high NRP2 levels in the subject can be used as a diagnostic biomarker that indicates that the subject is afflicted with the inflammatory lung disease, and would thereby assist one of ordinary skill in the art during diagnosis by identifying the presence of the inflammatory lung disease in a specific patient, allowing that person of ordinary skill in the art to initiate disease treatment strategies, such as the method of Mendlein.
Both Applicant's and the rejection's interpretations of the word "biomarker" are consistent with one of ordinary skill in the art’s understanding of the term. Since the rejection's interpretation and use of the term "biomarker" is consistent with that understood in the art, there would have been a motivation for one of ordinary skill in the art to use the NRP2 levels as a diagnostic biomarker as the rejection states.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander M Duryee whose telephone number is (571)272-9377. The examiner can normally be reached Monday - Friday 9:00 am - 5:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Louise Humphrey can be reached on (571)-272-5543. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/Alexander M Duryee/Examiner, Art Unit 1657
/LOUISE W HUMPHREY/Supervisory Patent Examiner, Art Unit 1657
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