RESPONSE TO APPLICANT’S AMENDMENT
1. Applicant's amendment, filed 12/10/2025, is acknowledged.
2. Claims 1, 5, 8-14, 18-27, 33-34, 37, 42-43, and 45 are pending.
3. Claims 8-11, 14, 21, 26-27,33-34 and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.
4. Claims 1, 5, 12-13, 18-20, 22-25, 37, 42 and 45 are under examination as they read on the following species:
(i) A1AT deficiency in a subject with less than about 80% normal serum levels;
(ii) the method does not require the step of determining A1AT levels;
(iii) — shortness of breath;
(iv) the method does not require administering an additional agent;
(v) the method can comprise the step of determining NE levels or activity, in a blood or serum sample;
(vi) SEQID NO: 2 with an N-linked glycan at residue at residue N45 and an O-linked glycan at residue T17 (DM300);
(vii) the ulinastatin polypeptide does not require an Fc region;
(viii) NE-inhibitor activity;
(ix) the method can comprise intravenous (IV) administration.
5. Applicant’s IDS, filed 12/11/2025, is acknowledged.
6. The following claims stand objected to for the following informalities:
The recitation between the parenthesis (….) in claims 13 and 20, is objected to because it is not clear whether the material between the parenthesis is claimed or not claimed.
The following new grounds of rejection are necessitated by the amendment submitted 12/10/2025.
8. 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 therefore, subject to the conditions and requirements of this title".
Claims 19-20 and 22 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 claims recite conditional treatment if the sample has increased NE levels or activity relative to a reference standard or healthy control, administer the pharmaceutical composition. 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 judicial exception for the reasons that follow.
The instant claims exclude the A1AT deficiency treatment if the level/activity of NE is low.
In its non-precedential decision in INO Therapeutics LLC v. Praxair Distribution Inc., the Federal Circuit agreed with the district court that method of treatment claims reciting “excluding” specific patients from treatment were ineligible for patenting under 35 USC § 101.
The court states that:
Applying this [Alice/Mayo] test, we agree with the district court that claim 1 of the ’741 patent is ineligible. It is undisputed that treatment of infants experiencing hypoxic respiratory failure with iNO gas has existed for decades. The inventors observed an adverse event that iNO gas causes for certain patients. The patent claim does no more than add an instruction to withhold iNO treatment from the identified patients; it does not recite giving any affirmative treatment for the iNO-excluded group, and so it covers a method in which, for the iNO-excluded patients, the body’s natural processes are simply allowed to take place. Consequently, the claim here is directed to the natural phenomenon. The claim, apart from the natural phenomenon itself, involves only well-understood, routine, and conventional steps.
Claim 19 is conditional claim. The claims require treating with Ulinastatin polypeptide of SEQ ID NO: 2 IF the level/activity of NE is increased relative to a reference standard or healthy control. Thus, the claims do not fall under the guidance provided by the Office in the Vanda Memo related specifically to treatment claims.
Further, the claims include the comparison of the NE levels/activity to a reference activity standard or healthy control. The unpatentability of abstract ideas was confirmed by the U.S. Supreme court in Bilski v. Kappos, No. 08-964, 2010 WL 2555192 (June 28, 2010) and in Alice Corp. V. CLS Bank Int’l, 134 S.Ct 2347, 2354 (2014). Applicant attention is directed to the association for Molecular Pathology (AMP) and ACLU v. USPTO and Myriad Genetics (Fed. Cir. 2012) at 56-57. Accordingly, the claims are directed to judicial exceptions.
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). While the claim practically apply the recited law of nature / natural phenomenon by including a step of administering a particular drug (i.e.,Ulinastatin polypeptide) to the subject to treat a particular disorder (i.e., A1AT deficiency) correlated with the increase NE levels/activity, however, the administration is conditional. The full scope of the claimed invention reads on not administering the drug when the level/activity of NE is low relative to a reference standard or healthy control. Thus, the claim includes methods in which the level of NE level/activity is not increase relative to a reference standard or healthy control. The claims do not clearly integrate the judicial exception into a practical application.
Therefore, whether viewed individually or as an ordered combination, the claims here do not recite a patent-eligible application under the second step of Mayo/Alice.
10. The following is a quotation of 35 U.S.C. 112(a) (Pre-AIA 35 U.S.C. 112, first paragraph):
(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.
11. Claims 1, 5, 12-13, 18-20, 22-25, 37, 42 and 45 stand rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as containing subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention for the same reasons set forth in the previous Office Action mailed 6/12/2025.
The claims are directed to a genus of method of treating the symptoms of or inhibiting the progression of A1AT-deficiency in subjects including A1AT-deficiency include any one or more of asthma, bronchiectasis, cirrhosis, COPD, respiratory failure, and vasculitis using a genus of ulinastatin polypeptide of SEQ ID NO: 2.
Applicant’s arguments, filed 12/10/2025, have been fully considered, but have not been found convincing.
Applicant traverses and submits that the instant specification provides a reasonable correlation between the exemplified activity of the claimed ulinastatin polypeptides and the treatment of A1AT-deficiency.
Applicant submits that the claimed ulinastatin polypeptides have been shown to directly bind to and inhibit NE with an IC50 in the low nanomolar range, a characteristic that is analogous to other approved therapeutics used to treat A1AT-deficiency. A1AT-deficiency results from a lack of A1AT, a serine protease that directly binds to and inhibits NE. In the absence of A1AT, NE can contribute to the degradation of lung tissue among other pathologies. Indeed, A1AT itself (e.g., Prolastin®-C) is used to treat certain A1AT-deficient diseases in part because of its direct NE- binding and inhibitor activity. In this context, it is reasonable to expect therapeutic activity from an alternate polypeptide with an analogous mechanism - that is, an alternate polypeptide that likewise directly binds to and inhibits NE. That reasonable expectation is further bolstered if the alternate polypeptide it has been shown to do so with an IC50 in the low nanomolar range.
Such is the case for the ulinastatin polypeptides of the instant claims, which have been unexpectedly shown to directly bind to and inhibit NE with an IC50 in the low nanomolar range, as described in Example 1 of the specification. Indeed, an in vitro assay of this type is especially valuable in establishing the direct binding and inhibitory effects of ulinastatin against NE, in contrast to in some in vivo assays which do not necessarily eliminate potential indirect mechanisms, such as indirect effects on "NE release".
Thus, in the least, Applicant's in vitro data of direct NE-binding and inhibition by
ulinastatin establishes a mechanism of action that is analogous to existing, approved agents in this therapeutic space, and thereby reasonably correlates the use of the claimed ulinastatin polypeptides with methods of treating AlAT-deficiency.
Applicant therefore submits that the unexpected biological activity of ulinastatin described in Example 1 provides a reasonable correlation between the disclosure in the specification and the treatment of AlAT-deficiency.
The Ulinastatin inhibition approach is distinct from the Prolastin-C treatment in several ways. In the case in which Prolastin augment serum levels with intravenous infusions of plasma-derived A1AT by increasing the serum A1AT levels and function to substitute for the impair A1AT deficiency. On the other hand, in the case of ulinastatin which is protease inhibitor that inhibits neutrophil elastase (NE) and suppresses the release of elastase from neutrophils which have distinct in structure, clinical application, and mechanism from Prolastin (A1AT). Accordingly, the mechanism of action is not analogous mechanism and the correlation between ulinastatin and Prolastin is distinct.
Importantly, Qiu et al (Chin Med J (Engl). 2015; 128(23):3138-3142) teach that ulinastatin (urinary trypsin inhibitor [UTI]) did not improve postoperative outcomes in our patients after cardiopulmonary bypass surgery (abstract). Qiu et al concluded that our data do not show that UTI can improve the outcome or attenuate the inflammatory response after cardiac surgery. Thus, a suspended question has been put forward that the comparative trials powered for important clinical end points are needed before routine administration of UTI (last ¶).
Uchida et al (Acute Med Surg 5, 90–97 (2018) teach that ulinastatin did not reduce mortality in elderly multiple organ failure patients: a retrospective observational study in a single center ICU.
Feng et al (Acute Care Surg 80, 335–340 (2016) teaches showed no statistical difference on mortality between ulinastatin and control groups.
Regarding in vivo methods which rely on generally unpredictable mechanisms, ''The amount of guidance or direction needed to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art.'' In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970). The “amount of guidance or direction'' refers to that information in the application, as originally filed, that teaches exactly how to make or use the invention. The more that is known in the prior art about the nature of the invention, how to make, and how to use the invention, and the more predictable the art is, the less information needs to be explicitly stated in the specification. In contrast, if little is known in the prior art about the nature of the invention and the art is unpredictable, the specification would need more detail as to how to make and use the invention in order to be enabling (MPEP 2164.03).'' The MPEP also states that physiological activity can be considered inherently unpredictable.
Further, in Rasmusson v. SmithKline Beecham Corp., 75 USPQ2d 1297-1303 (CAFC 2005), the court states “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.”
12. The previous103 rejections are withdrawn for the following reasons:
A. Claims 1, 2, 12, 19-20, 22-24, 37, 42, 45 stand rejected under 35 U.S.C. 103 as being unpatentable over Cleveland Clinic (10/19/2020) and/or Torres-Duran et al (Orphanet J Rare Dis. 2018 Jul 11;13:114), and/or Silverman et al (N Engl J Med 2009,360-2749-57, IDS-71) and/or Sandhaus and Turino (COPD, 10(S1):60-63, 2013, IDS-70) and/or Stockley RA. (Chronic Obstr Pulm Dis 2020; 7: 163–171), each in view of Hiyama et al (J Cardiothorac Vasc Anesth . 1997 Aug;11(5):580-4) or US20210277090A1 (IDS-28).
B. Claims 18 and 42 are rejected under 35 U.S.C. 103 as being unpatentable over Cliveland Clinic (10/19/2020) and/or Torres-Duran et al (Orphanet J Rare Dis. 2018 Jul 11;13:114), and/or Silverman et al (N Engl J Med 2009,360-2749-57, IDS) and/or Sandhaus and Turino (COPD, 10(S1):60-63, 2013, IDS) and/or Stockley RA. (Chronic Obstr Pulm Dis 2020; 7: 163–171), each in view of Hiyama et al (J Cardiothorac Vasc Anesth . 1997 Aug;11(5):580-4) or US20210277090A1 (IDS-28), applied to claims 1, 2, 12, 18-20, 22-24, 31-32, 37, 42, 45, above and further in view of Liao et al (Chinese Journal of Traumatology 21(6): 323-328, 2018).
Applicant statement pursuant to 35 USC §102(b)(2)(C) establishing that, not later than the effective filing date of the claimed invention, the subject matter disclosed in the US20210277090A1 (IDS-28) publication and presently claimed subject matter were either owned by Applicant, DiaMedica USA inc., or subject to any obligation of assignment to Applicant is sufficient to establish exception under 102(b)(2)(C) as commonly owned disclosure and therefore the `090 publication is not available as art under 35 USC §102(a)(2).
Claims SEQ ID NO: 2 is mutant human ulinastatin mature protein fragment (S10A), the prior art dose not teach the full length of SEQ ID NO: 2 comprising S10A mutation. Hiyama et al (J Cardiothorac Vasc Anesth . 1997 Aug;11(5):580-4) teaches ulinastatin but no mention of S10A mutation as claimed in SEQ ID NO:2.
13. The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
14. Claims 1, 5, 12-13, 18-20, 22-25, 37, 42 and 45 stand rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11725043.
Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of `043 patent are directed to methods of treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a therapeutic composition comprising mature ulinastatin, thereby treating the inflammatory disease or condition in the subject, wherein the inflammatory lung conditions is a pulmonary infection, pneumonia, infectious interstitial pneumonia associated with mixed connective tissue disease, pulmonary fibrosis, or acute respiratory distress syndrome.
The mechanism of action does not have a bearing on the patentability of the invention if the invention was already known or obvious. Even though applicant has proposed or claimed the mechanism by which ulinastatin polypeptide alleviates symptoms of pulmonary infection, pneumonia, pulmonary fibrosis, acute respiratory distress syndrome does not appear to distinguish the prior art teaching the same or nearly the same methods to achieve the same endresult. Mere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention. In re Wiseman, 201 USPQ 658 (CCPA 1979). Granting a patent on the discovery of an unknown but inherent function would remove from the public that which is in the public domain by virtue of its inclusion in, or obviousness from, the prior art. In re Baxter Travenol Labs, 21 USPQ2d 1281 (Fed. Cir. 1991). See M.P.E.P. 2145.
The claims of the `043 patent anticipate the instant claims.
Applicant’s arguments, filed 12/10/2025, have been fully considered, but have not been found convincing.
Applicant submits that the instant claims are directed to a specific disease indication within the broader genus of indications disclosed and claimed in the '043 patent. Moreover, as discussed herein, the selection of "A1AT-deficiency" as the specific diseases indication is directly connected to Applicant's unexpected discovery that ulinastatin directly binds to and inhibits NE with an IC50 in the low nanomolar range. It is well-established that a newly- discovered mechanism of action for a therapeutic agent can contribute to patentability if it directs a person of ordinary skill in the art to select a specific, previously-unconsidered disease indication for that agent. Such is the case here.
This not found persuasive because the Alpha-1 antitrypsin deficiency (AATD) increases the risk for lung and liver diseases including emphysema/COPD and liver issues like cirrhosis, liver cancer and the `043 patent teaching treating such disease with ulinastatin those of skill in the art would have a reason to target such diseases with the ulinastatin taught by the `043 patent with reasonable expectation of success. The `043 patent and the instant claims uses identical ulinastatin, binding to and inhibiting NE in vivo would be inherent in the absence of evidence to the contrary.
15. No claim is allowed.
16. The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
US 9856310 B2 teaches amino acids sequences of the UTI comprising S10A variants (SEQ ID NO: 72, ¶0114]) However, SEQ ID NO: 9 is 3 amino acids shorter than claimed SEQ ID NO: 2 (147 aa long).
Qy 1 AVLPQEEEGAGGGQLVTEVTKKEDSCQLGYSAGPCMGMTSRYFYNGTSMACETFQYGGCM 60
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 1 AVLPQEEEGAGGGQLVTEVTKKEDSCQLGYSAGPCMGMTSRYFYNGTSMACETFQYGGCM 60
Qy 61 GNGNNFVTEKECLQTCRTVAACNLPIVRGPCRAFIQLWAFDAVKGKCVLFPYGGCQGNGN 120
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Db 61 GNGNNFVTEKECLQTCRTVAACNLPIVRGPCRAFIQLWAFDAVKGKCVLFPYGGCQGNGN 120
Qy 121 KFYSEKECREYCGVPGDGDEELLR 144
||||||||||||||||||||||||
Db 121 KFYSEKECREYCGVPGDGDEELLR 144
17. Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
18. Any inquiry concerning this communication or earlier communications from the examiner should be directed to MAHER M HADDAD whose telephone number is (571)272-0845. The examiner can normally be reached on Monday-Friday from7:00AM to 4:30PM. If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Misook Yu, can be reached at telephone number 571-272-0839. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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January 20, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644