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 .
Application Status
2. Applicant’s amendment and response has been reviewed by the examiner and entered of record in the file. In this reply, claims 4 and 24 are canceled, and claims 1, 5, 6, and 12 are amended.
3. The scope of the independent invention encompassing the elected compound was previously defined as follows:
a method of treating acute kidney injury as associated with sepsis or a renal ischemia reperfusion injury in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the AKR1A1 inhibitor imirestat.
4. The remaining non-elected species remain withdrawn from consideration, pursuant to 37 CFR 1.142(b) as being drawn to nonelected subject matter, without traverse, there being no allowable generic or linking claim, i.e., claims 10, 11, and 15-19 are withdrawn.
5. Claims 1, 5, 6, 8, 12, 13, 22 and 23 are under examination with the elected species and are the subject of this office action.
Priority
6. The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed provisional application, Application No. 62/689,416, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. Application No. 62/689,416 does not have support for the recited limitation(s) of preventing or treating acute kidney injury, comprising administering the AKR inhibitor imirestat to the subject. Therefore Applicant’s instant claims are afforded benefit of priority to Application PCT/US2019/038982, filed June 25, 2019.
Specification
7. The substitute abstract submitted June 2, 2026 is sufficient to overcome the previous objection of the disclosure.
Previous Claim Rejections - 35 USC § 112
8. Claims 1, 4-6, 8, 12, 13, 22 and 23 were previously 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.
9. In view of Applicant’s amendments to narrow the genus of AKR1A inhibitors, the previous rejection for failing to comply with written description is withdrawn.
10. Claims 1, 5, 6, 8, 12, 13, 22 and 23 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treating acute kidney injury as a result of ischemia reperfusion injury by inhibiting AKR1A1, comprising administering the elected compound species and those embodied by the instant Specification, is not considered enabled for treating acute kidney injury comprising administering any/ all of the genus of selective AKR1A1 inhibitors embraced by the claims. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
11. This rejection has been modified as a result of Applicant’s amendment to the claims.
12. The standard for determining whether the Specification meets the enablement requirement was cast in the Supreme Court decision of Mineral Separation v. Hyde, 242 U.S. 261 (1916) which postured the question: is the experimentation needed to practice the invention undue or unreasonable? As recognized by the court in In re Wands, 858 F.2d 731 (Fed. Cir. 1988), that is still the standard to be applied, determined by consideration of the Wands factors (MPEP 2164.01(A)); namely, nature of the invention, breadth of the claims, guidance of the specification, the existence of working examples, state of the art, predictability of the art and the amount of experimentation necessary. All of the Wands factors have been considered, with the most relevant factors discussed below:
1) the quantity of experimentation necessary,
2) the amount of direction or guidance provided,
3) the presence or absence of working examples,
4) the nature of the invention,
5) the state of the prior art,
6) the relative skill of those in the art,
7) the predictability of the art, and
8) the breadth of the claims.
13. These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons.
14. Nature of the Invention: As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.”
In the instant case, the claims are drawn to a method of treating acute kidney injury in a subject in need thereof, comprising: administering to the subject any AKR1A1 inhibitor(s) that is/are embraced by the claims.
15. The state of the prior art, level of predictability and relative skill level: As stated in MPEP 2164.05(a), “[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.”
As discussed above, the instantly claimed invention pertains to a method of treating acute kidney tissue injury in a subject in need thereof, comprising: administering to the subject an AKR1A1 inhibitor embraced by the genus of the claims.
16. The relative skill of those in the art is high, that of an MD or PhD. That factor is outweighed, however, by the unpredictable nature of the art. As illustrative of the state of the art, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised. This is certainly true in the case of aldo-keto reductase (AKR) inhibitors which, as disclosed by Penning, embrace a vast scope of 16 AKR families, including AKR1A1 (aldehyde reductase). However, Penning (Chemico-Biological Interactions 2015) teaches that AKR inhibitors have demonstrated significant unpredictability in research and development: “Isoform specific inhibitors of the human enzymes are required to target specific diseases with the understanding that off-target effects may occur when these compounds bind to related AKRs; a lack of appreciation for the similarity in AKR structure– function could lead to the failure of therapeutic leads.” (see abstract; page 238, left column, first paragraph; and page 244, right column, last paragraph).
17. The amount of direction or guidance provided and the presence or absence of working examples: The amount of direction provided by the Applicant is considered to be determined by the Specification and the working examples. In the instant case, the specification provides no direction or guidance for the use of all of the aforementioned inhibitors in treating any/all tissue injury “associated with ischemia reperfusion injury.” No reasonably specific guidance is provided concerning useful therapeutic protocols for said disclosed compounds, other than Imirestat itself.
18. Applicant demonstrates in the specification, Example at pages 70-86, that knockout SCoR-/- and/or PKM2 mice had greater renoprotection against acute kidney injury, however the Specification is silent to the administration of any inhibitor of AKR1A1 for the actual treatment of acute kidney injury. Because genetic silencing completely ablates the gene while pharmacological inhibition may still cause interaction of said protein with other co-binding partners, no real conclusion can be made as to the effectiveness of the protein inhibition of SCoR with respect to treating, let alone preventing, acute kidney injury. Applicant has not demonstrated that any inhibitor of AKR1A1 shows efficacy for treating, any type of acute kidney injury, in vitro or in vivo.
19. The breadth of the claims: As stated in MPEP 2164.01(c), “[w]hen a compound or composition claim is limited by a particular use, enablement of that claim should be evaluated based on that limitation.” Thus, as stated in MPEP 2164.08, “[t]he focus of the examination inquiry is whether everything within the scope of the claim is enabled” (emphasis added). Indeed, the Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without ‘undue experimentation’.” In re Wright, 999 F.2d 1557 (Fed. Cir. 1993) (emphasis added). At the same time, however, it is also recognized that not everything necessary to practice the invention need be disclosed. Nor is it necessary that an Applicant test all the embodiments of his invention. In re Angstadt, 537 F.2d 498 (CCPA 1976) (emphasis added). In fact, as stated by the court in In re Buchner, 929 F.2d 660 (Fed. Cir. 1991), a patent need not teach, and preferably omits, what is well known in the art.
20. Accordingly, for purposes of enablement, the relevant concern is whether the scope of enablement provided to one skilled in the art by the disclosure is commensurate in scope with the protection sought by the claims. Thus, while “a patent application is entitled to claim his invention generically” it is necessary that “he provide a disclosure sufficient to enable one skilled in the art to carry out the invention commensurate with the scope of his claims". Amgen, Inc, v. Chugai Pharmaceutical Co., Ltd. (Fed. Cir. 1991). As noted by the court in In re Fisher, 427 F.2d 833 (CCPA 1970), the scope of enablement must bear a “reasonable correlation” to the scope of the claims. See also Ak Steel Corp. v. Sollac, 344 F.3d 1234 (Fed. Cir. 2003) and In re Moore, 439 F.2d 1232 (CCPA 1971). As stated in MPEP 2164.08, resolution of this concern requires two stages of inquiry: “[t]he first is to determine how broad the claim is with respect to the disclosure. The entire claim must be considered. The second inquiry is to determine if one skilled in the art is enabled to make and use the entire scope of the claim without undue experimentation”.
21. As to the first inquiry, as discussed above, the claims are thus very broad insofar as they are directed to the treatment of acute kidney injury in a subject in need thereof, comprising: administering to the subject an AKR1A1 inhibitor embraced by the genus of the instant claims. While such “treatment” might theoretically be possible utilizing Imirestat or the Imirestat analogue delineated in Fig. 6, as a practical matter it is nearly impossible to achieve treatment for said disease with every possible alternative AKR1A1 inhibitor embraced by the claims.
22. The instant Specification discloses only one working example of acute kidney injury in knockout SCoR -/- and/or PKM2 mice (pages 70-86), and does not disclose the administration of any AKR1A1 inhibitor whatsoever. As such, the claims are broad with respect to the disclosure. The second inquiry is discussed in detail below.
23. The amount of experimentation necessary: In view of all of the foregoing, at the time the invention was made, it would have required undue experimentation to practice the entire scope of the invention as claimed. As discussed above, the claims are drawn to a method of treating acute kidney injury in a subject in need thereof, comprising: administering to the subject any AKR1A1 inhibitor presently embraced by the claims.
24. Since identifying any compound which is capable of modulating the activity of a specific receptor, ion channel, or enzyme is extremely complex, the nature of the instant invention considered to be one of extreme complexity. In the instant case, this complexity is exacerbated by the broadness of the AKR1A1 inhibitors encompassed by the claims with respect to the disclosure since the scope of said inhibitors encompasses over a dozen compound species, whereas the instant Specification fails to disclose the administration of any such compound species exerting the disclosed activity. Although the relative skill of those in the art to which the invention pertains is high, the state of the art and unpredictability within the art is such that even the most talented artisan could not reasonably predict which compounds encompassed by the claims would exert the alleged activity based on the limited disclosure. Although the skilled artisan would have known that certain chemical modifications to the disclosed compounds may predictably provide structurally related compounds having similarly activity, the skilled artisan would have also known that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. As evidenced by Penning, above, aldo-keto reductase inhibitors, in particular, demonstrate significant unpredictability, i.e., “a lack of appreciation for the similarity in AKR structure– function could lead to the failure of therapeutic leads.” Thus, given the unpredictability of AKRs in particular, it is highly unpredictable whether any inhibitor within the genus of compounds encompassed by the claims based on the instant disclosure would, in fact, be usable. Whether the other compounds encompassed by the claims would be usable is even less predictable. As such, the only way to ascertain which claimed compounds presently encompassed by the claims are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
Response to Arguments
25. Applicant argues that the 35 U.S.C. § 112, first paragraph, scope of enablement, rejection should be withdrawn because claim 1 has been amended to recite the use of imirestat or specific imirestat analogues (as described in paragraph [0133] of the specification) in a method of treating acute kidney injury as a result of sepsis or a renal ischemia reperfusion injury in a subject in need thereof.
26. Applicant's arguments have been fully considered but they are not persuasive. While it is agreed that imirestat and certain analogues thereof are described in the Specification at paragraph [0133], Applicant has not demonstrated support for a method of treating acute kidney injury as a result of sepsis or a renal ischemia reperfusion injury in a subject in need thereof, comprising administering a selective or partially selective AKR1A1 inhibitor embraced by the genus recited in the claims. The instant Specification discloses only one working example of acute kidney injury in knockout SCoR -/- and/or PKM2 mice (pages 70-86), and does not disclose the administration of any AKR1A1 inhibitor whatsoever.
The state of the art is that Stamler (U.S. 20170360755 A1) specifically names imirestat as the selective or partially selective AKR1A1 inhibitor (see paragraphs [0084]-[0085]) for treating ischemic-reperfusion injury due to renal ischemia (paragraphs [0149] and [0151]).
However, a method of treatment comprising administering the other AKR1A1 inhibitors presently embraced by claim 1 is not supported by the art or the disclosure.
Accordingly, the scope of enablement rejection is maintained.
Previous Claim Rejections - 35 USC § 103
27. The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
28. Claims 1, 5, 6, 8, 13, 22 and 23 remain rejected under 35 U.S.C. 103(a) as being unpatentable over Stamler, Jonathan, U.S. 20170360755 A1, in view of Zager et al., (Am. J. Physiol. Renal Physiol 2006).
29. This rejection has been modified as a result of Applicant’s amendment to the claims.
It is noted that the disclosure of the prior-filed provisional application, Application No. 62/689,416, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for the recited limitation(s) of preventing or treating a tissue injury associated with ischemia reperfusion injury in a subject, wherein the tissue injury is acute kidney injury, comprising administering the AKR inhibitor imirestat to the subject. Therefore Applicant’s instant claims are afforded benefit of priority to Application PCT/US2019/038982, filed June 25, 2019.
Claim 1, as amended, is directed to a method for treating acute kidney injury as a result of sepsis or a renal ischemia reperfusion injury in a subject in need thereof, the method comprising administering to the subject a therapeutically effective amount of selective or partially selective AKR1A1 inhibitor, (more specifically, imirestat:
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), more specifically wherein the AKR1A1 inhibitor is administered at an amount effective to promote S-nitrosylation of proteins in the subject, and wherein the AKR1A1 inhibitor is not an ADH3 inhibitor (claim 13).
30. Stamler teaches and recites a method of treating disorders associated with NO/SNO (nitric oxide adducts called S-nitrosothiols or “SNO”) deficiency or benefiting from increased SNO in a subject in need thereof, the method comprising: administering to the subject an AKR inhibitor at an amount(s) effective to promote S-nitrosylation of proteins in the subject, wherein the inhibitor is not ADH3 (see Stamler Claim 1), more specifically wherein the AKR inhibitor is an AKR1A1 inhibitor that is imirestat (see Stamler Claims 2 and 3). Stamler teaches the selectivity for AKR1A1: “the AKR1A1 inhibitor can have a selectivity for AKR1A1 versus AKR1B1≧10 times” and specifically names imirestat as the selective or partially selective AKR1A1 inhibitor (see paragraphs [0084]-[0085]).
31. Stamler goes on to teach that the method can be used to treat ischemic-reperfusion injury, and specifically names renal ischemia (paragraphs [0149] and [0151]).
32. Stamler is silent to the treatment of acute kidney injury in said subject.
33. However, Zager et al. suggest that acute renal failure (aka acute kidney injury) is characterized by excess iNOS activity/protein nitrosylation (See abstract). Zager et al. teach that NO hyperproduction with increased protein nitrosylation appears to be concomitant with acute renal failure (page F555, left column, second paragraph).
34. As such, one skilled in the art before the effective filing date of the claimed invention would reasonably consider that by virtue of administering the selective AKR1A1 inhibitor imirestat, which promotes S-nitrosylation of proteins in the subject, one is necessarily treating acute kidney injury in said subject. It would have been obvious to one of skill in the art before the effective filing date of the claimed invention to administer the selective AKR1A1 inhibitor imirestat to a subject in need thereof to treat acute kidney injury associated with renal ischemic-reperfusion injury in said subject.
Thus, claims 1 and 13 are prima facie obvious.
Claim 5 is drawn to claim 1, and limits wherein the amount of AKR1A1 inhibitor, administered to the subject is an amount effective to induce renal vasodilatation, enhance resistance to hypoxia, improve renal hemodynamics, decrease renal oxidative stress, reduce renal inflammation, and/or preserve renal function.
35. Stamler additionally teaches other conditions or disorders associated with ischemia that are “suitable for treatment or amelioration using the methods described herein” including renal ischemia, inflammation, hypoxia, ischemic renal disease, and vascular disease of the kidney. Thus, by virtue of administering the selective AKR1A1 inhibitor to a subject, one of skill in the art before the effective filing date of the claimed invention would reasonably expect a reduction in renal inflammation, and/or a preservation of renal function in said subject.
As such, claim 5 is prima facie obvious.
Claim 6 is drawn to claim 1 and limits wherein the AKR1A1 inhibitor is administered before and/or after the ischemia reperfusion injury.
Claim 8 is drawn to claim 1, wherein the AKR1A1 inhibitor is administered at least about 2 hours before and/or at least about 30 minutes after acute kidney injury.
36. Stamler teaches that the AKR1A1 inhibitor can be administered before or after onset of the unwanted condition, disease, or unwanted state:
“[i]f it is administered prior to clinical manifestation of the unwanted condition (e.g., disease or other unwanted state of the host animal) then the treatment is prophylactic, i.e., it protects the host against developing the unwanted condition, whereas if it is administered after manifestation of the unwanted condition, the treatment is therapeutic,”
(paragraph 0053]). And, dose regimen optimization is clearly a result effective parameter that a person of ordinary skill in the art would routinely optimize given the guidance of the prior art. Thus it would have been obvious for a person of ordinary skill in the art before the effective filing date of the claimed invention to optimize a parameter of a known method, i.e., timing of administration such that the AKR1A1 inhibitor is administered several hours prior to acute kidney injury (such as when renal ischemia starts) or about 30 minutes after the onset of renal ischemia, with a reasonable expectation of success.
As such, claims 6 and 8 are prima facie obvious.
Claim 22 is drawn to claim 1, further comprising administering nicotinamide adenine dinucleotide (NAD+) and/or a NAD+ precursor in combination with the selective or partially selective AKR1A1 inhibitor.
Claim 23 is drawn to claim 22, wherein the NAD+ precursor is selected from the group consisting of tryptophan, nicotinic acid, nicotinic acid riboside, nicotinamide riboside (NR), and nicotinamide (NAM).
37. Stamler teaches combining the AKR1A1 inhibitor with an additional agent selected from an ADH inhibitor (paragraph [0157]), and discusses alternative ADH inhibitors in paragraphs [0093]-[0096]. In particular, Stamler discloses the ADH inhibitors isonicotinic acid (a position isomer of nicotinic acid), and CNAD (5-beta-D-ribofuranosylnicotinamide adenine dinucleotide), (i.e., an isomeric and isomeric analogue of NAD), (paragraphs [0093] and [0095]). As the isotonic acid and CNAD compounds are both disclosed as ADH inhibitors and therefore have the same utility as the recited nicotinic acid and nicotinamide adenine dinucleotide (NAD+), respectively, and are generally sufficiently similar in structure, there is a presumed expectation that such compounds possess similar properties. In re Wilder, 563 F.2d 457, 195 USPQ 426 (CCPA 1977). See also In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978) (stereoisomers prima facie obvious); Aventis Pharma Deutschland v. Lupin Ltd., 499 F.3d 1293, 84 USPQ2d 1197 (Fed. Cir. 2007) (5(S) stereoisomer of ramipril obvious over prior art mixture of stereoisomers of ramipril). Thus one of skill in the art before the effective filing date of the claimed invention would have been motivated to combine said either of said ADH inhibitors with imirestat in the method of treatment disclosed by Stamler, because one would have reasonably expected that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
As such, claims 22 and 23 are prima facie obvious.
38. Claim 12 is rejected under 35 U.S.C. 103(a) as being unpatentable over Stamler, Jonathan, U.S. 20170360755 A1, in view of Zager et al., (Am. J. Physiol. Renal Physiol 2006), as applied to claims 1, 5, 6, 8, 13, 22 and 2, above, and further in view of Wang and Bellomo, (Nature Reviews: Nephrology 2017).
Claim 1 is addressed in detail, above.
Claim 12 is drawn to claim 1, and limits wherein the method prevents or treats acute kidney injury associated with cardiovascular surgery.
39. Stamler in view of Zager et al. suggest the treatment of acute renal injury associated with renal ischemic-reperfusion injury in a subject (characterized by excess iNOS activity/protein nitrosylation) comprising administering the selective AKR1A1 inhibitor imirestat, which promotes S-nitrosylation of proteins, to said subject, but do not teach wherein the acute kidney injury is associated with cardiovascular surgery.
40. Yet, Wang teaches acute kidney injury associated with cardiovascular surgery (“CSA-AKI”), i.e.:
“CSA-AKI is the most common clinically important complication in adult patients undergoing open heart surgery, and is associated with increased mortality and morbidity. In patients in intensive care units, CSA-AKI is the second most common type of AKI after septic AKI.” (see abstract)
Wang goes on to dicuss ischemia-reperfusion injury:
“Several major injury pathways are probably involved in the development of CSA-AKI, including hypoperfusion, ischaemia–reperfusion injury, neuro humoral activation, inflammation, oxidative stress, nephrotoxins and mechanical factors. All of these injury pathways can occur preoperatively, intraoperatively and postoperatively, or at all of these times, and to varying degrees in any given patient.” (page 2, right column, last two sentences, through page 3, left column, first sentence).
41. As such, one skilled in the art before the effective filing date of the claimed invention would have been motivated to treat acute kidney injury associated with cardiovascular surgery, as a result of renal ischemia-reperfusion injury in a subject in need thereof, comprising administering the AKR1A1 inhibitor imirestat, with a reasonable expectation of success.
Thus, claim 12 is prima facie obvious.
Response to Arguments
42. Applicant traverses the previous obviousness rejection of Stamler and Zager et al. because Stamler and Zager et al., alone or in combination, fail to teach or suggest that a selective or partially selective AKR1A1 inhibitor, such as imirestat, can be administered at an amount effective to treat AKI resulting from sepsis or a renal ischemia reperfusion injury in a subject. Applicant argues the following points:
(a) Applicant argues that Stamler broadly discloses that an AKR1A1 inhibitor is used for the treatment of disorders caused by the deficiency of NO/SNO. Applicant contends that while Stamler laundry lists reperfusion injury (e.g., traumatic muscle injury in heart or lung or crush injury) [00147], ischemic-reperfusion injury [0149], and renal ischemia [0149], [0151], as disorders that can be treated with an AKR inhibitor, Stamler fails to describe the treatment of an AKI resulting from sepsis or a renal ischemia reperfusion injury and/or disclose experimental results showing a selective or partially selective AKR1A1 inhibitor, such as imirestat, effective for any sepsis associated AKI, renal ischemia reperfusion injury or renal ischemia.
43. Applicant's arguments have been fully considered but they are not persuasive. In response to Applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). In this case, Stamler is relied upon for disclosing the administration to the subject an AKR inhibitor at an amount effective to promote S-nitrosylation of proteins in the subject, more specifically wherein the AKR inhibitor is an AKR1A1 inhibitor that is imirestat (Stamler claims 1-3), and suggests that said S-nitrosylation of proteins can be used to treat ischemic-reperfusion injury, specifically naming renal ischemia (paragraphs [0149] and [0151]). Zager is relied upon for suggesting that acute renal failure (acute kidney injury) is characterized by excess iNOS activity/protein nitrosylation (abstract), such that one of skill in the art would reasonably consider that by mitigating excess protein nitrosylation, one is treating acute kidney failure.
44. Regarding the comprehensiveness of disorders disclosed as treatable with an AKR1A1 inhibitor, and the scope of AKR1A1 inhibitors, disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments. In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971). "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 554, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994) (The invention was directed to an epoxy impregnated fiber-reinforced printed circuit material. The applied prior art reference taught a printed circuit material similar to that of the claims but impregnated with polyester-imide resin instead of epoxy. The reference, however, disclosed that epoxy was known for this use, but that epoxy impregnated circuit boards have "relatively acceptable dimensional stability" and "some degree of flexibility," but are inferior to circuit boards impregnated with polyester-imide resins. The court upheld the rejection concluding that applicant’s argument that the reference teaches away from using epoxy was insufficient to overcome the rejection since "Gurley asserted no discovery beyond what was known in the art." 27 F.3d at 554, 31 USPQ2d at 1132.). Furthermore, "[t]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Therefore, nothing unobvious is seen in one of skill in the art selecting imirestat for the treatment of renal ischemia-reperfusion injury in a subject in need thereof, with a reasonable expectation of success.
(b) Applicant argues that Zager et al. demonstrates that acute renal failure is marked by increased iNOS-mediated NO production and resulting protein nitrosylation and characterizes this NO hyperproduction and consequent nitrosative stress as a central pathological process, but fails to teach the effective treatment of AKI resulting from sepsis or a renal ischemia reperfusion injury (or experimental results).
Applicant argues that Zager et al. teach that NO hyperproduction with increased protein nitrosylation appears to be concomitant with acute renal failure (pg. F555, left column, second paragraph), however, Zager et al. identifies increased protein nitrosylation as a marker of damage rather than a protective mechanism, indicating that promoting this process could actually worsen kidney injury. Applicant alleges that the teachings of Zager et al. frame the hyper-production of nitric oxide as a key component of destructive nitrosative stress and mitochondrial dysfunction, such that the ordinary artisan would not reasonably consider using a selective AKR1A1 inhibitor like imirestat to treat AKI, as promoting protein S-nitrosylation would likely be viewed as counterproductive or even harmful. Applicant contends that because Zager et al. appear to suggest the possibility that the promotion of S-nitrosylation could actually worsen kidney injury, an ordinary artisan could not have a reasonable expectation that administering a selective AKR1A1 inhibitor would be effective for the treatment of AKI, let alone AKI resulting from sepsis or a renal ischemia reperfusion injury.
45. Applicant's arguments have been fully considered but they are not persuasive. Regarding Applicant’s allegation that Zager’s teaching of promoting the process of S-nitrosylation could actually worsen kidney injury, a reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill the art, including nonpreferred embodiments. Merck & Co. v. Biocraft Laboratories, 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert. denied, 493 U.S. 975 (1989). See also Upsher-Smith Labs. v. Pamlab, LLC, 412 F.3d 1319, 1323, 75 USPQ2d 1213, 1215 (Fed. Cir. 2005)(reference disclosing optional inclusion of a particular component teaches compositions that both do and do not contain that component); Celeritas Technologies Ltd. v. Rockwell International Corp., 150 F.3d 1354, 1361, 47 USPQ2d 1516, 1522-23 (Fed. Cir. 1998) (The court held that the prior art anticipated the claims even though it taught away from the claimed invention. "The fact that a modem with a single carrier data signal is shown to be less than optimal does not vitiate the fact that it is disclosed.").
46. Thus, the argument that Zager “appear[s] to suggest the possibility that the promotion of S-nitrosylation could actually worsen kidney injury” does not negate the fact that Zager demonstrates that acute renal failure is marked by the mechanism of increased iNOS-mediated NO production and resulting protein nitrosylation. As such, nothing unobvious is seen in one of skill in the art targeting S-nitrosylation in order to treat acute kidney injury in a subject in need thereof.
Terminal Disclaimer
47. The terminal disclaimer filed on June 3, 2026, disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of U.S. Patent No. 11,351,155 B2 has been reviewed and is accepted. The terminal disclaimer has been recorded.
Previous Double Patenting Rejections
48. Claims 1, 4, and 13, were previously rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4 and 7 of U.S. Patent No. 11,351,155 B2 in view of Zager et al., (Am. J. Physiol. Renal Physiol 2006).
49. In view of Applicant’s submission of the terminal disclaimer over U.S. Patent No. 11,351,155 B2 on June 3, 2026, the previous double patenting rejections are withdrawn.
Conclusion
50. In conclusion, claims 1, 5, 6, 8, 10-13, 15-19, and 22-23 are present in the application. Claims 10, 11, and 15-19 are presently withdrawn from consideration. Claims 1, 5, 6, 8, 12, 13, 22 and 23 are rejected. No claim is currently allowable.
51. 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.
52. Any inquiry concerning this communication or earlier communications from the examiner should be directed to JANET L COPPINS whose telephone number is (571)272-0680. The examiner can normally be reached Monday-Friday 8:30AM-5PM EST.
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, Amy L Clark can be reached on 571-272-1310. 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.
/JANET L COPPINS/Examiner, Art Unit 1628
/Rayna Rodriguez/Primary Examiner, Art Unit 1628
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