DETAILED ACTION
1. A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 04/22/2026 has been entered.
2. Claims 1, 5, 8-14, 21, 33-34, 42-43, and 45 are pending.
3. Claims 8-11, 14, 21, 33-34 and 43 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to nonelected inventions.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, 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. 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.
6. Claims 1, 5, 12-13, 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 and 01/23/2026.
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.
Factors to be considered in determining whether undue experimentation is required to practice the claimed invention are summarized In re Wands (858 F2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)). The factors most relevant to this rejection are the scope of the claim, the amount of direction or guidance provided, the lack of sufficient working examples, the unpredictability in the art and the amount of experimentation required to enable one of skill in the art to practice the claimed invention.
The Alpha-1 antitrypsin deficiency animal model was not available as a platform testing of ulinastatin polypeptides before the effective filing date of the instant application to test the effect of the claimed ulinastatin polypeptide on the claimed asthma, bronchiectasis, cirrhosis, COPD, respiratory failure, and vasculitis.
The specification does not reasonably provide enablement for a method for the treatment, ameliorating the symptoms of , or inhibiting the progression of, alpha-1 antitrypsin (A1AT) deficiency in a subject with ulinastatin polypeptide. 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 or use the invention commensurate in scope with the claim.
The exemplification in the specification is limited to in vitro inhibition of neutrophil elastase using recombinant ulinastatin (DM300), SEQ ID NO: 2. Neutrophil elastase activity was measured using the Neutrophil Elastase Colorimetric Drug Discovery Assay (Enzo Life Sciences). Inhibitor was added to a final reaction concentration at 100, 31.6, 10, 3.16, 1, 0.316, 0.1, 0.0316, or 0 µg/mL DM300 by addition of 20 µl of 5 x concentration of DM300 diluted in assay buffer, followed by 10 µl of diluted neutrophil elastase. 100 µM elastatinal was also included as a control. Under the tested conditions, the Ic50 for DM300 was about 3.153 µg/ml or about 43.78 nM. The specification discloses that the recombinant ulinastatin (e.g., DM300) has potential therapeutic utility as an inhibitor of neutrophil elastase activity, for example, in the treatment of neutrophil elastase (NE)-associated diseases such as alpha-1 antitrypsin (A1AT) deficiency (see Example 1).
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.”
Furthermore, because any treatment using ulinastatin and ulinastatin variants having the ability of protease inhibitor activity in vivo is not yet known and has not yet been disclosed, therefore, the method is only potential because it is not currently available in practical form. Therefore, the disclosure of mechanisms mediating alpha-1 antitrypsin (A1AT) deficiency does not provide sufficient guidance to a method of alpha-1 antitrypsin (A1AT) deficiencies treatment in vivo.
However, in view of the lack of predictability of the art to which the invention pertains the lack of established clinical protocols for effective A1AT deficiency therapies, undue experimentation would be required to practice the claimed methods with a reasonable expectation of success, absent a specific and detailed description in applicant’s specification of how to effectively practice the claimed methods and absent working examples providing evidence which is reasonably predictive that the claimed methods are effective for.
It is not clear on the basis of in vitro studies, how to reliably predict in vivo relevance of treating neutrophil elastase (NE)-associated diseases such as alpha-1 antitrypsin (A1AT) deficiency. Furthermore, even when in vivo studies have been performed, the resultant data are inconsistent. One major reason for the perplexing inconsistencies in this filed is that currently available animal models are not good predictors of human disease.
Results obtained under controlled conditions and in inbred animals often differ from the clinical response obtained in patients. This applies in particular to strategies based on responses, including strategies drawn to treating A1AT deficiency in a subject.
The specification fails to provide an animal model to study the effect of the claimed ulinastatin polypeptides.
The specification does not teach how to extrapolate data obtained from in vitro studies to the development of effective in vivo subject therapeutic treatment, commensurate in scope with the claimed invention. Thus in the absence of working examples or detailed guidance in the specification, the use of the ulinastatin polypeptides comprising SEQ ID NO: 1 or 2 are fraught with uncertainties. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to use in humans or animals. Ex parte Maas, 9 USPQ2d 1746.
Given the relatively incomplete understanding in correlating in vitro assays and in vivo animal models to clinical treatment of A1AT deficiency involved, and the lack of a reasonable correlation between the narrow disclosure in the specification and the broad scope of protection sought in the claims, the claims are not enabled. See MPEP 2164.08
If the use disclosed is of such nature that the art is unaware of successful treatments with chemically analogous compounds, a more complete statement of how to use must be supplied.
The determination that "undue experimentation" would have been needed to make and use the claimed invention is not a single, simple factual determination. Rather, it is a conclusion reached by weighing all the above noted factual considerations. In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir. 1988).
If the use disclosed is of such nature that the art is unaware of successful treatments with chemically analogous compounds, a more complete statement of how to use must be supplied.
" The scope of the required enablement varies inversely with the degree of predictability involved, but even in unpredictable arts, a disclosure of every operable species is not required. A single embodiment may provide broad enablement in cases involving predictable factors, such as mechanical or electrical elements...However, in applications directed to inventions in arts where the results are unpredictable, the disclosure of a single species usually does not provide an adequate basis to support generic claims.” MPEP § 2164.03.
"Substantiating evidence may be in the form of animal tests which constitute recognized screening procedures with clear relevance to utility in humans. See Ex parte Krepelka, 231 USPQ 746 (Board of Patent Appeals and Interferences 1986) and cases cited therein." Ex parte Maas, 9 USPQ2d 1746.
"First, although appellants' specification describes certain in vitro experiments, there is no correlation on this record between in vitro experiments and a practical utility in currently available form for humans or animals. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to utility in humans or animals" (emphasis added). Ex parte Maas, 9 USPQ2d 1746.
"There is no evidence of record that experimental animal models have been developed in this area which would be predictive of human efficacy." Ex parte Balzarini, 21 USPQ2d 1892.
Reasonable correlation must exist between the scope of the claims and scope of the enablement set forth. In view on the quantity of experimentation necessary the limited working examples, the nature of the invention, the state of the prior art, the unpredictability of the art and the breadth of the claims, it would take undue trials and errors to practice the claimed invention.
Applicant's arguments, filed 4/22/2026, have been fully considered, but have not been found
convincing.
Applicant submits that although the foregoing invention has been described in some detail by way of illustration and example for purposes of clarity of understanding, it will be readily apparent to one of ordinary skill in the art in light of the teachings of this invention that certain changes and modifications may be made thereto without departing from the spirit or scope of the appended claims. The following examples are provided by way of illustration only and not by way of limitation. Those of skill in the art will readily recognize a variety of noncritical parameters that could be changed or modified to yield essentially similar results. Applicant submits that a skilled artisan would readily appreciate that the examples in the instant application are provided for exemplary purposes, and should not be interpreted as unduly limiting the instantly claimed invention.
Applicant submits that the skilled artisan would recognize that the instant application provides ample disclosure on preparing ulinastatin polypeptides and on using ulinastatin polypeptides toward treating, ameliorating the symptoms of, or inhibiting the progression of, alpha-1 antitrypsin (AlAT) deficiency. For examples, see [0073-0079], [0084-0102], and [0150-0153]. In view of such sufficient guidance, the skilled artisan would readily be able to make the ulinastatin polypeptide and test it toward the use of the instantly claimed method.
Applicant submits that the skilled artisan would appreciate that the instant application provides ample demonstration that exemplary ulinastatin polypeptides can be prepared and show inhibition activities toward neutrophil elastase. For example, Example 1 of the instant application discloses the use of a Neutrophil Elastase Colorimetric Drug Discovery Assay to measure the ability of the claimed ulinastatin polypeptide to inhibit NE. Table El and Figure 1 demonstrate ulinastatin inhibition of NE across eight concentrations, providing working examples of the use of ulinastatin polypeptides. In particular, Table El quantifies the dose-dependent inhibition of NE by ulinastatin, reporting an IC50 of 3.153 pg/ml with an R2 of 0.9484, thereby confirming potent and reproducible NE inhibitor activity. Table U1 also identifies the ulinastatin sequences employed, and the specification mentions that "[m]ethods for determining NE levels and/or activity are known in the art (see, for example, Shoemark et al., Eur Respir J. 53(6):1900303, 2019)."
Applicant submits that a skilled artisan would recognize that AlAT is a primary endogenous inhibitor of NE, and that AlAT deficiency results in dysregulated, elevated NE proteolytic activity leading directly to tissue damage. See, e.g., McCarthy et al., "The Role of Neutrophils in Alpha-1 Antitrypsin Deficiency", Annual American Thoracic Society, Vol. 13, Supp. 4, pp. 5297-5304, Aug 2016. The specification also provides teachings regarding the role of NE in disease pathology. For example, the specification describes that "[e]xcess activity of neutrophil elastase and similar proteases has been reported to cause tissue damage and to alter the remodeling process in many lung conditions such as pneumonia, respiratory distress, and acute lung injury (Polverino et al., Chest. 152(2):249- 262, 2017), and skin conditions such as bullous pemphigoid (Liu et al., J Clin Invest. 105(1):113- 123, 2000)" (Specification at pp.1-2) and that "AlAT is produced in the liver, and one of its functions is to protect the lungs from neutrophil elastase, an enzyme that can disrupt connective tissue" (Specification at p. 14).That is, in view of the exemplary data disclosed in the instant application, and the general biology framework in the field, the skilled artisan would appreciate that the instant application readily provides a reasonable expectation of successfully using the instantly claimed ulinastatin polypeptide toward treating, ameliorating the symptoms of, or inhibiting the progression of, alpha- 1 antitrypsin (AlAT) deficiency.
This is not found persuasive because the undue experimentation line is crossed when the amount of trial-and-error or research required is unreasonable in light of the invention and the state of the art. In fact, the Supreme Court has reaffirmed that a reasonable amount of experimentation can be allowed. As stated in Amgen Inc. et al. v. Sanofi et al., “[w]hat is reasonable in any case will depend on the nature of the invention and the underlying art.” For example, a small amount of testing to confirm a known technique might be fine, but if the patent basically says “figure it out for yourself” or requires a research program to fill in gaps, that likely falls on the wrong side of the line. The enablement requirement refers to enabling the full scope of the claims, not just one way of doing the invention or a subset of embodiments. If significant inventive effort or guesswork is still needed to practice parts of the claimed invention, the disclosure is not enabling. As discussed above the prior art before the filing date of the invention was unpredictable.
The Alpha-1 antitrypsin deficiency animal model comprising the claimed mutations and phenotypes and genotypes was not available as a platform testing of ulinastatin polypeptides before the effective filing date of the instant application to test the effect of the claimed ulinastatin polypeptide on the claimed asthma, bronchiectasis, cirrhosis, COPD, respiratory failure, and vasculitis. In the absence of A1At deficient animal model, those skilled in the art would not be able to test the claimed ulinastating polypeptides toward the claimed in vivo methods of treating, ameliorating the symptoms of, or inhibiting the progression of, alpha-1 antitrypsin (A1AT) deficiency including any one or more of asthma, bronchiectasis, cirrhosis, COPD, respiratory failure, and vasculitis having shortness of breath, wheezing, sputum production, or recurrent respiratory infections.
The specification does not teach how to extrapolate data obtained from in vitro studies to the development of effective in vivo subject therapeutic treatment, commensurate in scope with the claimed invention. Thus, in the absence of working examples or detailed guidance in the specification, the use of the ulinastatin polypeptides comprising SEQ ID NO: 1 or 2 are fraught with uncertainties. It is not enough to rely on in vitro studies where, as here, a person having ordinary skill in the art has no basis for perceiving those studies as constituting recognized screening procedures with clear relevance to use in humans or animals. Ex parte Maas, 9 USPQ2d 1746.
The specification fails to disclose any dosages for use in treating, ameliorating the symptoms of, or inhibiting the progression of, alpha-1 antitrypsin (A1AT) deficiency in a subject. Therefore, the specification also fails to provide any working examples. The prior art of Qiu et al, Uchida et al and Feng et al cited above shows unpredictable of ulinastatin in the in vivo treatment. In view of the intractable nature and unpredictability of treating, ameliorating the symptoms of, or inhibiting the progression of, alpha-1 antitrypsin (A1AT) deficiency in a subject and the lack of guidance with respect to in vivo and the lack of working examples, one skilled in the art could not use the inventions without undue experimentation.
7. 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.
8. Claims 1, 5, 12-13, 37, 42 and 45 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 23-29 of copending Application No. 18338970 (now allowed but not issued yet) (reference application) in view of Strnad et al (New England Journal of Medicine 382(15):p 1443-1455, April 9, 2020).
The claims of the `970 application are directed to methods of treating acute pancreatitis in a subject in need thereof, comprising administering to the subject a therapeutic composition comprising an isolated, mature ulinastatin polypeptide, comprising (i) SEQ ID NO: 2, (ii) an N-linked glycan at residue at residue N45, and (iii) an O-linked glycan at residue T17, the residues being defined by SEQ ID NO: 2, and a pharmaceutically-acceptable carrier, thereby treating the acute pancreatitis in the subject.
The `970 application further claims method of treating an inflammatory disease or condition in a subject in need thereof, comprising administering to the subject a therapeutic composition comprising an isolated, mature ulinastatin polypeptide, comprising (i) SEQ ID NO: 2, (ii) an N-linked glycan at residue at residue N45, and (iii) an O-linked glycan at residue T17, the residues being defined by SEQ ID NO: 2, and a pharmaceutically-acceptable carrier., thereby treating the inflammatory disease or condition in the subject.
The claims of the `970 application differs from the claimed invention only in the target subpopulation/group of alpha-1 antitrypsin (A1AT) deficiency in a subject.
Strnad teaches 95% of severe cases of AAT deficiency result from the homozygous substitution of a single amino acid, Glu342Lys (the Z allele). Mild AAT deficiency typically results from a different amino acid replacement, Glu264Val (the S allele). However, many other alleles have been described that have variable effects, such as a lack of protein production (null alleles), production of misfolded protein, or no effect on the level or function of circulating AAT (Table 1). AAT is synthesized in the liver and secreted into the circulation, where its primary role is to protect lung tissue against attack by the enzyme neutrophil elastase. Point mutations can lead to retention of AAT in the liver, causing liver disease through a toxic “gain of function,” whereas the lack of an important circulating proteinase inhibitor predisposes homozygotes with severe deficiency to early-onset emphysema (“loss of function”). The high frequency of genetic variants suggests that AAT mutations confer a selective advantage, perhaps by amplifying the inflammatory response to invasive respiratory and gastrointestinal infection. Strnad et al review the current understanding of the pathophysiology of AAT deficiency and discuss how this knowledge has led to new therapeutic strategies (abstract). The key longitudinal, population-based cohort study of AAT deficiency followed 127 persons with the PI ZZ genotype and 54 with the PI SZ genotype from birth to 45 years of age. Cholestatic jaundice developed in 10% of infants with the PI ZZ genotype. Persons in the cohort study who had the PI ZZ genotype and had a history of tobacco smoking had hyperinflation and emphysema at 37 to 39 years of age, whereas age matched adults with the PI MM genotype who had never smoked did not have evidence of hyperinflation and emphysema (see page 1447, left col).
Strnad teaches that the PI MZ genotype (i.e., heterozygous Z carriage) is a common form of AAT deficiency, occurring in up to 4% of the population with Euro pean ancestry. These persons are susceptible to multiple disorders (Table 2), partly due to lower levels of circulating AAT but also because the secreted Z AAT is less effective at inhibiting neutrophil elastase. Studies enriched for persons at risk have shown that PI MZ carriers have a clear predisposition to COPD, at least among smokers. PI MZ carriers have an increased incidence of gallstone disease and an increased susceptibility to immune disorders such as ANCA-associated vasculitis (see page 1448, right col. And Table 2). Strnad teaches AAT deficiency is underdiagnosed, and it is important not merely to consider the condition but also to test specific patient groups for AAT deficiency. All persons with COPD, liver disease, poorly responsive asthma, c-ANCA vasculitis (in >90% of cases, the antibody is specific for proteinase 3), panniculitis, or bronchiectasis, in addition to first-degree relatives of people with AAT deficiency, should be tested. The first step in testing is measurement of the AAT level in serum. This measurement should be accompanied by an assessment of C-reactive protein, since AAT is an acute-phase reactant that increases during infection or inflammation (see pg 1449, under Lung disease and Fig. 1).
Those of skill in the art would have had a reason to target the AAT deficiency subject taught by Strnad using the treatment taught by the `970 application because like the subject taught by the `970 application, AAT deficiency increase inflammation.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
9. Claims 1, 5, 12-13, 37, 42 and 45 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-27 of U.S. Patent No. 11725043 in view of Strnad et al (New England Journal of Medicine 382(15):p 1443-1455, April 9, 2020).
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 claims of the `970 application differs from the claimed invention only in the target subpopulation/group of alpha-1 antitrypsin (A1AT) deficiency in a subject.
The teachings of Strnad et al have been discussed, supra.
Those of skill in the art would have had a reason to target the AAT deficiency subject taught by Strnad using the treatment taught by the `043 patent because like the subject taught by the 043 patent, AAT deficiency increase inflammation.
Applicant’s arguments, filed 4/22/2026, have been fully considered, but have not been found convincing.
Applicant requests that the rejection be held in abeyance until otherwise patentable subject matter is identified in the claims.
The rejection is maintained until it is fully addressed.
10. No claim is allowed.
11. The art made of record and not relied upon is considered pertinent to applicant's disclosure:
(i) Inoue et al. inflammatory Diseases-A modern Perspective (2011); Dr. Amit Nagal (Ed.), Ch. 1, pgs. 1-14, pages 15.
Inoue et al teach UTI, also referred to as ulinastatin, HI-30, ASPI, or bikunin, is an acidic glycoprotein, wherein during inflammation, UTI is cleaved from I αI family proteins through proteolytic cleavage by neutrophil elastase in the peripheral circulation or at the inflammatory site. Therefore, plasma UTI has been considered to be one of the acute phase reactions and indeed, the plasma UTI level and its gene expression alter in severe inflammatory conditions. UTI appears to prevent organ injury by inhibiting the activity of these proteases. Based on the multivalent nature of protease inhibition, clinically, UTI is widely used, especially in Japan, to treat acute pancreatitis including post-endoscopic retrograde cholangiopancreatography pancreatitis, in which proteases are thought to play a pathophysiological role (see Section 2).
Fig. 1 shows glycosylation sites: The shaded ovals labeled CHO (i.e., S10 and N45) indicate carbohydrate attachment sites. These represent the points where the protein is modified with sugar chains (glycans), making it a glycoprotein.
Inoue et al teach that UTI has a protective effect against ischemia reperfusion injury in the liver , kidney, heart, and lung in vivo via the actions of its radical scavenging elements. In humans, prepump administration (5,000 U/kg) of UTI reportedly improves cardiopulmonary bypass-induced hemodynamic instability and pulmonary dysfunction through the attenuation of IL-6 and IL-8 production/release in humans (see section 3). Inoue et al provide results indicate that UTI also protects against acute lung inflammation induced by the intratracheal administration of LPS, at least in part, via the local suppression of proinflammatory cytokines and oxidative stress, suggesting that UTI may be a therapeutical tool for acute lung injury in humans (section 4.3). Inoue et al teaches that plasma UTI levels increase in patients with acute hepatitis and markedly decrease in those with fulminant hepatitis, suggesting that the plasma UTI level is closely linked to the severity of liver damage. Further, the plasma UTI level is reportedly correlated with the degree of liver damage in patients with chronic liver diseases such as liver cirrhosis (section 4.4).
(ii) Awan et al (Lung Pulm Respir Res J. 2018; 2(1):115).
Awan et al teach recurrent acute pancreatitis secondary to alpha-1-antitrypsin deficiency which justify routine testing for alpha-1-antitrypsin deficiency in patients with recurrent acute pancreatitis of unknown aetiology and may warrant further studies in to alpha-1-antitrypsin replacement as a novel therapeutic target for a subset of patients with troublesome pancreatitis (abstract).
12. 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.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). 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) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
June 22, 2026
/MAHER M HADDAD/ Primary Examiner, Art Unit 1644
Prosecution Insights