Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
DETAILED ACTION
The amendment dated 30 January 2026, in which claims 20, 23, 26-29 have been amended, and claims 22, 25, 30-32, 34 have been cancelled, is acknowledged.
Claims 19-21, 23, 26-29, 33, 35, 36 are pending in the instant application.
Claim 19 is withdrawn, as being drawn to a non-elected invention.
Claims 20-21, 23, 26-29, 33, 35, 36 are examined herein.
Response to arguments of 30 January 2026
In view of Applicant’s amendment of 30 January 2026, all the objections and rejections to claims 22, 25, 30-32, 34 are herein withdrawn. Claims 22, 25, 30-32, 34 have been cancelled.
In view of Applicant’s amendment of 30 January 2026, the objection to the Title is herein withdrawn. A minor typographical error was corrected.
The objections to claims 20 and 35 are herein maintained; Applicant did not clarify the claim language.
On 30 January 2026, Applicant has amended claim 20 to recite preventing, treating and/or alleviating cerebral ischemic stroke associated with gastrointestinal ischemia-reperfusion.
The rejection of claims 20-23, 25-36 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite, is herein withdrawn. New rejections are made below, based on Applicant’s amendment of 30 January 2026.
Applicant’s arguments (Remarks of 30 January 2026, pages 6-8) against the rejection of claims 20-22, 25-27, 30-32, 34, 36 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Wang et al. (CN 108484431); against the rejection of claims 20, 22, 25-28, 30-31, 35, 36 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Williamson et al. (US 5,710,181); and against the rejection of claims 20, 22, 25-28, 30-32, 34, 36 under 35 U.S.C. 102(a)(1) as being anticipated by Danielisova, have been considered.
On 30 January 2026, Applicant has amended claim 20 to recite a method of treating cerebral ischemic stroke. In view of this amendment, the rejection of claims 20, 22, 25-28, 30-31, 35, 36 under 35 U.S.C. 102(a)(1) and 102(a)(2) over Williamson is herein withdrawn. Williamson teaches a method of treating IBD, not cerebral ischemic stroke.
Applicant’s Declaration under 37 CFR 1.132, signed by co-inventor Hongwei Zhou, submitted on 30 January 2026, has been considered.
Inventor Zhou explains (point 3, Declaration) the now claimed “ischemic stroke associated with gastrointestinal ischemia reperfusion” is different from general strokes and different from the ischemic stroke described in the prior art references.
Inventor Zhou explains (point 4, Declaration) that in clinical trials, the recruited ischemic stroke patients were divided into two groups based on the presence or absence of "gastrointestinal ischemia-reperfusion" symptoms: namely
"gastrointestinal ischemia-reperfusion-related ischemic stroke" and
"non-gastrointestinal ischemia-reperfusion-related ischemic stroke" (i.e., general ischemic stroke).
Inventor Zhou provides additional data (point 4, Declaration) showing (Figure 1) that the two groups were characterized by different Enterobacteriaceae abundance in the intestines, different neurological function scores, and different degree of neurological function recovery 7 days after the onset of the disease.
Inventor Zhou concludes (point 5, Declaration), based on the data in Figure 1, that compared with the "non-gastrointestinal ischemia-reperfusion-related ischemic stroke" group, the patients with "gastrointestinal ischemia-reperfusion-related ischemic stroke" exhibited a higher abundance of Enterobacteriaceae in the intestines; in addition, their disease severity was more serious (with higher neurological function scores), and the recovery of neurological function 7 days after the onset was significantly reduced.
Inventor Zhou explains (point 6, Declaration) that mice with experimentally induced stroke can also be classified into these two disease types, the "non-gastrointestinal ischemia-reperfusion-related ischemic stroke" group, and those with "gastrointestinal ischemia-reperfusion-related ischemic stroke", with expression levels of the nos2 gene, nox1 gene, and duox2 gene in the two groups of mice being different (Figure 2).
Inventor Zhou states (point 7, Declaration) that the results in Figure 2 indicate that compared with the "non-gastrointestinal ischemia-reperfusion-related ischemic stroke" group, the expression levels of genes related to oxidative stress (nos2 gene, nox1 gene, duox2 gene) in the intestines of the hosts with "gastrointestinal ischemia-reperfusion-related ischemic stroke" were significantly increased. The increased expression levels of these genes suggest the occurrence of ischemia-reperfusion in the intestines. Furthermore, the results in Figure 2 once again verify that the hosts with "gastrointestinal ischemia-reperfusion- related ischemic stroke" exhibit a higher abundance of Enterobacteriaceae in the intestines, and their degree of brain injury is more severe.
Inventor Zhou concludes (point 8, Declaration) that, based on the above experimental results, it can be confirmed that "gastrointestinal ischemia-reperfusion-related ischemic stroke" is different from general "ischemic stroke".
As a note, the text for Figures 1 and 2 is unintelligible/too small to read. It seems that Figure 1 refers to human patients, while Figure 2 refers to mice. However, it is unclear whether, for example in Figure 1, the level of Enterobacteriaceae in the intestines is measured before treatment. How are the patients divided into the groups? Are they patients who suffered stroke and had their level of Enterobacteriaceae in the intestines measured – before, during or after treating the stroke with an iNOS inhibitor?
Regarding Figure 2, which refers to mice, how were the levels of nos2 gene, nox1 gene or duox2 gene measured- were they measured in mice who suffered cerebral stroke, but before treatment, during treatment or after treatment?
Applicant seems to argue that patients with gastrointestinal ischemia-reperfusion related cerebral ischemic stroke are different from those with cerebral ischemic stroke (no gastrointestinal ischemia-reperfusion) because they have more serious disease severity, longer recovery, and are characterized by higher levels of Enterobacteriaceae in the intestines and higher levels of Nox1 gene in the intestine (pre-treatment or during treatment or after treatment?).
Yet, NOS inhibitors are known to be effective to treat each of the two conditions, cerebral ischemic stroke and gastrointestinal ischemia-reperfusion.
Importantly, the term cerebral ischemic stroke associated with gastrointestinal ischemia-reperfusion in claim 20 is not defined. It can be interpreted as ischemic stroke that causes gastrointestinal ischemia-reperfusion. Or it can interpreted as ischemic stroke caused by gastrointestinal ischemia-reperfusion. Or the two conditions can be present at the same time in the patient, are co-morbid.
If the scenario involves 1) patients with cerebral ischemic stroke that causes gastrointestinal ischemia-reperfusion, treating the cerebral ischemic stroke with iNOS inhibitors known to treat cerebral ischemic stroke (Wang, Danielisova) is expected to result in therapeutic effect, while reducing/alleviating/preventing any resulting gastrointestinal ischemia-reperfusion caused by the cerebral ischemic stroke. Monitoring for inflammation markers in the intestine could be an obvious step, given the gut-brain axis teachings of Ayra.
In 2) patients with gastrointestinal ischemia-reperfusion that causes cerebral ischemic stroke, treating the gastrointestinal ischemia-reperfusion with iNOS inhibitors known to treat gastrointestinal ischemia-reperfusion (Boracelli) is expected to result in therapeutic effect, while preventing the injury caused by the gastrointestinal ischemia-reperfusion, namely cerebral ischemic stroke.
Since the same iNOS inhibitor treats both conditions, administration of the same drug is expected to inherently have therapeutic effect on both cerebral ischemic stroke and gastrointestinal ischemia-reperfusion in a subject.
Applicant argues (Remarks of 30 January 2026, page 7) that in Example 2 Specification, the subject suffers from cerebral ischemic stroke using the mouse MCAO model; then, as in Example 3, it is observed that the cecal blood flow decreased in the subject indicating ischemia-reperfusion occurs in the intestines. Additionally, Applicant measures an increase in Nox1, Nos2, Duox2 genes and in the nitrate concentration in intestinal samples (Examples 4, 5).
Applicant argues (page 7) that by inhibiting activity of NOS locally in the GI tract, the expression levels of in Nox1, Nos2, Duox2 genes decrease, i.e. treating of cerebral ischemic stroke caused by gastrointestinal ischemia-reperfusion.
These arguments are not persuasive. It is unclear how and why the instant method is distinct from the teachings of prior art. Prior art teaches administering an iNOS inhibitor to the same patient population- the very same animal model of cerebral stroke, MCAO, as in the instant Specification. Thus, the prior art teaches treating the same disease, which is cerebral stroke, using the same animal model, MCAO, with an inhibitor of NOS. Additionally, Applicant checks the ceccal blood flow and measures an increase in Nox1, Nos2, Duox2 genes and in the nitrate concentration in intestinal samples (Examples 4, 5) in the patients treated. Yet, such modifications in the ceccal blood flow and inflammation markers inherently occur, and measuring these markers is an obvious step (based on the brain-gut axis teachings in Arya) in the known method of treatment of cerebral stroke with a known iNOS inhibitor.
Applicant argues (page 7, last paragraph, page 8, first paragraph) that cerebral ischemic stroke leads to gastrointestinal ischemia reperfusion, which leads to changes in the intestinal tissue, which will lead to the deterioration of the ischemic stroke. This argument is acknowledged; however, these changes necessarily occur in a subject suffering from cerebral ischemic stroke. Further, Arya teaches the relationship between the brain and the gut in such patients.
Applicant argues (page 8, fourth paragraph)
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This argument is not persuasive. The prior art and the instant Specification use the very same animal model, MCAO, which is an animal model of cerebral ischemic stroke.
There is no distinction between the animal model in the prior art and the animal model used by Applicant in the Specification. As such, Applicant administers the very same therapeutic agent, iNOS inhibitor, to the very same patient population, cerebral ischemic stroke patients MCAO animal model.
Applicant presents similar arguments (page 9) against the rejection of the claims under 35 U.S.C. 103 over Danielisova, in view of Boracelli and Arya. The focus of the arguments is that the cited prior art does not teach cerebral ischemic stroke associated with gastrointestinal ischemia reperfusion, as now claimed.
This argument has been addressed above.
The rejections are herein maintained, and modified rejections are made below, based on Applicant’s amendment of 30 January 2026.
Claim objection
Claim 20 is objected to because the recitation “in a subject, comprising administering” could read --in a subject in need thereof, comprising administering.--
Claim 35 is objected to because it is unclear what is meant by “is formulated to adapt to oral administration”. Claim 35 could recite the method of claim 20, wherein the nitric oxide synthase pathway inhibitor is orally administered to the subject.
Claim 28 is objected to because, for better clarity, it could read “The method of claim 27, wherein the amino acid inhibitor is selected from […], […], and […]”. A separate claim could be added, drawn to “The method of claim 27, wherein the non-amino acid inhibitor is selected from […], […], and […].”
Claim Rejections- 35 USC 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 20, 21, 23, 26-29, 33, 35-36 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 20 fails to clearly and precisely set forth the manner in which the cerebral ischemic stroke is “associated with” gastrointestinal ischemia-reperfusion. Neither the claims nor the specification set forth the manner in which the cerebral ischemic stroke is “associated with” gastrointestinal ischemia-reperfusion. The Specification teaches (page 7, last paragraph) that the distal injury such as cerebral ischemic stroke occurs “during, before or after the gastrointestinal ischemia-reperfusion.” There is no explicit requirement that the two conditions, distant injury/cerebral ischemic stroke and GI ischemia reperfusion, are connected. It is unclear whether the instantly claimed method is intended for the treatment of gastrointestinal ischemia-reperfusion per se\ the treatment of distal injury/cerebral ischemic stroke caused by gastrointestinal ischemia-reperfusion; the treatment of gastrointestinal ischemia-reperfusion resulting from/caused by cerebral stroke; or the treatment of both cerebral stoke and gastrointestinal ischemia-reperfusion. It is unclear, for example, whether the distal injury/cerebral ischemic stroke is a symptom or a clinical manifestation of the GI ischemia-reperfusion. There is no explicit requirement in claim 20 that the subject be afflicted with GI ischemia-reperfusion (rather, only claim 33, which depends on claim 20, recites that the subject has experienced, is experiencing or is at risk of experiencing GI ischemia-reperfusion). The claims fail to clearly or precisely set forth the manner by which the cerebral ischemic stroke is “associated with” the recited gastrointestinal ischemia-reperfusion. Absent this information, the claim fails to set forth the metes and bounds of the subject matter for which Applicant is presently seeking protection.
Appropriate clarification of the claim language is required.
Claim 23 is indefinite because it recites (a) monitoring a GI condition in a subject, wherein said gastrointestinal condition comprises the expression level of Nos2, Nox1, and Duox2 genes and the concentration of nitrate and inflammatory factors in intestinal/colon tissues. How can an unknown, undefined by the claims, gastrointestinal condition “comprise” expression levels of Nox1 genes or concentration of inflammatory factors?
The claim seems to refer to monitoring or detecting a level of one or more markers or biological molecules. Claim 23 fails to define, however, what biomarker levels are being measured, reciting instead concentration of inflammatory factors in intestinal tissues. It is unclear what is being measured. There are large numbers of possible “inflammatory factors”. Further, the examiner notes that a change in the levels of biomarkers could indicate disease progression, disease regression, or merely a diagnosis of the condition. Further, it is noted that the levels of biomarkers measured vary in time (see also Fig. 3 Fig. 4). In other words, the instant claims appear to encompass any level of biomarker, as there may be no change in the level of a biomarker, depending upon the circumstances under which the standard or threshold level is established. It is unclear whether the levels of biomarkers are measured in intestinal tissues/biological sample from the subject who is currently undergoing the treatment of independent claim 20, or if the biological sample is from the subject providing a reference sample. One wishing to practice the instantly claimed invention would thus not recognize the metes and bounds for which Applicant seeks protection.
For these reasons, the metes and bounds of the present claims cannot be determined and one having ordinary skill in the art would not necessarily be reasonably apprised of the scope of the claims.
Claim 23 recites a gastrointestinal condition without specifying the GI condition monitored. As such, it is unclear what the relationship is between step (a) and step (b) /the gastrointestinal ischemia reperfusion in step (b). Further, since step (b) in claim 23 recites “when monitoring […], administering to the subject said nitric oxide synthase pathway inhibitor”, claim 23 seems to present the reader with a choice to administer the NOS inhibitor only when monitoring shows the subject is at risk […]. In other words, step (b) in claim 23 provides for the possibility that no administering occurs. Yet, claim 23 depends on claim 20, which recites administering to the subject a NOS inhibitor. As such, there is insufficient antecedent basis for step (b) of claim 23 (“when […], administering”), in claim 20 (which requires administering).
Further, in claim 23, a broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 23 recites the broad recitation intestinal tissues, and the claim also recites colon tissues which is the narrower statement of the range/limitation. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
Claim 29 is drawn to the method of claim 20, wherein said nitric oxide synthase pathway inhibitor is administered by administering the subject a drug, and the nitric oxide synthase pathway inhibitor in the drug has a concentration of about 0.0001% (w/w) to about 90% (w/w). The claim is unclear. It is unclear what the relationship is between “a drug” (which drug?) and the nitric oxide synthase pathway inhibitor; both seem to be administered; and one has a certain concentration in the other? Is the claim trying to define the concentration of the nitric oxide synthase pathway in a pharmaceutical composition administered? Applicant is required to clarify the claim language.
Appropriate clarification of the claim language is required.
Claim Rejections- 35 USC 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 20-21, 26-27, 36 are rejected under 35 U.S.C. 102(a)(1) and 102(a)(2) as being anticipated by Wang et al. (CN 108484431, published 4 September 2018, cited in IDS), as evidenced by Arya et al. (Brain Circulation 2018, 165-173, cited in PTO-892 of 30 October 2025).
Wang teaches a method of treating ischemic brain injury, as in instant claim 20, by administering to a subject in need thereof an inhibitor of inducible nitric oxide synthase (iNOS), as in instant claim 26; the iNOS inhibitor is a cinnamic acid compound, which is a non-amino acid inhibitor, as in instant claim 27.
Wang teaches that the cinnamic acid compound of the invention has strong anti-inflammatory effect, can effectively inhibit iNOS, and is effective to treat ischemic stroke, which is a disease of instant claims.
Wang teaches (Example 4) that 4-hydroxy-3-methoxy-cinnamoyl-L-tyrosine (compound 4) has in vivo anti-ischemic brain injury activity (in a rat ischemia reperfusion model, SD rats).
The rats were randomly divided into 4 groups, namely, the blank group, model group (MCAO group) MCAO + compound 4 (25 mg/kg) MCAO + compound 4 (50 mg/kg). Compound 4 is administered intragastrically, as in instant claim 21, for 15 consecutive days.
4-hydroxy - 3 - methoxy-cinnamoyl-L-tyrosine effectively reduced cerebral infarction area increase caused by ischemia reperfusion, dose-dependently.
Since Wang teaches intragastric administration of the iNOS inhibitor in the method of treating cerebral ischemic stroke, Wang implicitly teaches that the iNOS inhibitor is not substantially decomposed by digestive juices, as in instant claim 36. Further, it is noted that the stability of a compound in the presence of digestive juices is an inherent property of the iNOS inhibitor administered in the method of treatment.
While Wang does not explicitly teach that the iNOS inhibitor effective to treat cerebral stroke has a local effect in the gastrointestinal tract, as in instant claim 20, the claimed limitation appears to be a result or property of the administration of the effective amount of the iNOS inhibitor. As such, the claimed limitation appears to be met by the prior art. Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed method. In the absence of evidence to the contrary, the burden is on the applicant to prove that the function of the product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Even though Wang does not specifically teach that cerebral ischemic stroke is associated with gastrointestinal ischemia reperfusion, as in the instant claims, cerebral ischemic stroke is inherently associated with gastrointestinal ischemia reperfusion, as evidenced by Ayra. Arya teaches (figure 1) changes in the brain -gut-microbia axis after cerebral ischemic stroke, and the gut immune response to brain injury. Arya teaches (page 170, right column, second paragraph) that the GI tract contains >70% of inflammatory and immune cells in the body, and plays a key role in inflammatory and immune response after injury in remote organs including the brain. Arya teaches (page 170, right column, first paragraph) that the gut inflammatory and immune cells play a key role in the development of brain injury in cerebral stroke; migration of gut inflammatory and immune cells to the CNS has a significant impact on the brain damage severity and duration after stroke.
Since Wang teaches administration of the very same therapeutic agent, a NOS inhibitor, to the very same patient population, patients suffering from cerebral ischemic stroke/ MCAO animal model, to treat said patients, said NOS inhibitor, upon administration, will inherently elicit the same effect on cerebral ischemic stroke and associated gastrointestinal ischemia reperfusion as instantly claimed.
As such, claims 20-21, 26-27, 36 are anticipated by Wang.
Claims 20, 26-28, 36 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Danielisova et al. (Neurochem Res 2011, 36, 476-486, cited in IDS) as evidenced by Arya et al. (Brain Circulation 2018, 165-173, cited in PTO-892 of 30 October 2025).
Danielisova discloses a method of treating cerebral ischemic stroke, as in instant claim 20, by administering to a subject in need thereof aminoguanidine, which is a selective inducible nitric oxide synthase (iNOS) inhibitor (Abstract), as in instant claims 26-28.
While Danielisova does not explicitly teach that the iNOS inhibitor aminoguanidine effective to treat cerebral stroke has a local effect in the gastrointestinal tract, as in instant claim 20, the claimed limitation appears to be a result or property of the administration of the effective amount of the iNOS inhibitor aminoguanidine. As such, the claimed limitation appears to be met by the prior art. Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed method. In the absence of evidence to the contrary, the burden is on the applicant to prove that the function of the product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
While Danielisova does not specifically teach that aminoguanidine is not substantially decomposed by digestive juices, as in instant claim 36, the stability of a compound in the presence of digestive juices is an inherent property of the compound/aminoguanidine administered in the method of treatment.
Even though Danielisova does not specifically teach that cerebral ischemic stroke is associated with gastrointestinal ischemia reperfusion, as in the instant claims, cerebral ischemic stroke is inherently associated with gastrointestinal ischemia reperfusion, as evidenced by Ayra. Arya teaches (figure 1) changes in the brain -gut-microbia axis after cerebral ischemic stroke, and the gut immune response to brain injury. Arya teaches (page 170, right column, second paragraph) that the GI tract contains >70% of inflammatory and immune cells in the body, and plays a key role in inflammatory and immune response after injury in remote organs including the brain. Arya teaches (page 170, right column, first paragraph) that the gut inflammatory and immune cells play a key role in the development of brain injury in cerebral stroke; migration of gut inflammatory and immune cells to the CNS has a significant impact on the brain damage severity and duration after stroke.
Since Danielisova teaches administration of the very same therapeutic agent, NOS inhibitor aminoguanidine, to the very same patient population, patients suffering from cerebral ischemic stroke/ MCAO animal model, to treat said patients, said NOS inhibitor, upon administration, will inherently elicit the same effect on cerebral ischemic stroke and associated gastrointestinal ischemia reperfusion as instantly claimed.
As such, claims 20, 26-28, 36 are anticipated by Danielisova.
Claim Rejections- 35 USC 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 20-21, 26-29, 33, 35, 36 are rejected under 35 U.S.C. 103 as obvious over Danielisova et al. (Neurochem Res 2011, 36, 476-486, cited in IDS), in view of Boracelli et al. (Nitric oxide 2006, 14, 212-218, cited in IDS), in further view of Arya et al. (Brain Circulation 2018, 165-173, cited in PTO-892 of 30 October 2025).
Danielisova discloses a method of treating cerebral ischemic stroke, as in instant claim 20, by administering (i.p. injection page 477, left column, last paragraph, dose 150 mg/kg) to a subject in need thereof aminoguanidine, which is a selective inducible nitric oxide synthase (iNOS) inhibitor (Abstract), as in instant claims 26-28.
Danielisova does not teach gastrointestinal administration of aminoguanidine, as in instant claim 21, or oral administration, as in instant claim 35.
Danielisova does not teach that cerebral stroke is associated with gastrointestinal ischemia-reperfusion in the subject, as in instant claims, and does not teach monitoring the patient for gastrointestinal ischemia-reperfusion, as in instant claim 33, and administering the aminoguanidine to the patient during or after experiencing gastrointestinal ischemia-reperfusion, as in instant claim 23.
Boracelli et al. (Nitric oxide 2006, 14, 212-218, cited in IDS) teaches the selective inhibition of iNOS (as in instant claim 26) by administration of aminoguanidine prevents intestinal ischemia-reperfusion injury (Abstract).
Arya et al. (Brain Circulation 2018, 165-173) teaches the brain-gut axis after stroke. Arya teaches (figure 1) changes in the brain -gut-microbia axis after cerebral ischemic stroke, and the gut immune response to brain injury. Arya teaches (page 170, right column, second paragraph) that the GI tract contains >70% of inflammatory and immune cells in the body, and plays a key role in inflammatory and immune response after injury in remote organs including the brain. Arya teaches (page 170, right column, first paragraph) that the gut inflammatory and immune cells play a key role in the development of brain injury in a variety of CNS disease conditions, including stroke and TBI; migration of gut inflammatory and immune cells to the CNS may have a significant impact on the brain damage severity and duration after stroke.
While Danielisova does not explicitly teach that the iNOS inhibitor aminoguanidine effective to treat cerebral stroke has a local effect in the gastrointestinal tract, as in instant claim 20, the claimed limitation appears to be a result or property of the administration of the effective amount of the iNOS inhibitor aminoguanidine. As such, the claimed limitation appears to be met by the prior art. Applicants are reminded that the office does not have the facilities and resources to provide the factual evidence needed in order to establish that the product of the prior art does not possess the same material, structural and functional characteristics of the claimed method. In the absence of evidence to the contrary, the burden is on the applicant to prove that the function of the product is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
While Danielisova does not specifically teach that aminoguanidine is not substantially decomposed by digestive juices, as in instant claim 36, the stability of a compound in the presence of digestive juices is an inherent property of the compound/aminoguanidine administered in the method of treatment.
It would have been obvious to combine the teachings of Danielisova, Boracelli and Arya to arrive at the instant invention.
The person of ordinary skill in the art would have been motivated to administer aminoguanidine to a patient suffering from cerebral ischemic stroke in the method taught by Danielisova, and monitor for gastrointestinal ischemia reperfusion in said patient, because
Danielisova teaches that aminoguanidine is effective to treat cerebral ischemic stroke,
Arya teaches changes in the brain -gut-microbia axis after cerebral ischemic stroke, and Arya teaches that cerebral ischemic stroke and intestinal injury can be comorbid; and
Boracelli teaches that aminoguanidine prevents/treats intestinal ischemia-reperfusion injury.
Thus, the person of ordinary skill in the art would have administered aminoguanidine to a person suffering from cerebral ischemic stroke and comorbid intestinal injury, such as GI ischemia reperfusion injury, with the expectation that aminoguanidine is effective to treat both cerebral ischemic stroke and GI ischemia reperfusion in said patient.
The person of ordinary skill in the art would have administered aminoguanidine to the patient via gastrointestinal route, as in claim 21, orally, as in claim 35, because exploring different routes of administration of a known drug, in a known method of treatment, is well within the skill of the artisan. Regarding claim 29, the person of ordinary skill in the art would have optimized the concentration of aminoguanidine in the composition administered, because such optimization of concentration of active ingredient in a composition, in a known method of treatment, is well within the skill of the artisan.
As such, claims 20-21, 26-29, 33, 35, 36 are rejected as prima facie obvious.
Claims 20, 23 are rejected under 35 U.S.C. 103 as obvious over Danielisova et al. (Neurochem Res 2011, 36, 476-486, cited in IDS), in view of Boracelli et al. (Nitric oxide 2006, 14, 212-218, cited in IDS), Arya et al. (Brain Circulation 2018, 165-173, cited in PTO-892 of 30 October 2025), in further view of Bedard et al. (Physiol Rev 2007, 87, 245-313, cited in PTO-892).
Danielisova, Boracelli, Arya are as above.
Danielisova discloses a method of treating cerebral ischemic stroke, as in instant claim 20, by administering (i.p. injection page 477, left column, last paragraph) to a subject in need thereof aminoguanidine, which is a nitric oxide synthase (iNOS) inhibitor (Abstract).
Danielisova does not teach that cerebral stroke is associated with gastrointestinal ischemia-reperfusion in the subject, as in instant claims, and does not teach monitoring levels of Nos2, Nox1, Duox2 genes and inflammatory factors in intestinal tissue, monitoring the patient for gastrointestinal ischemia-reperfusion, and administering the aminoguanidine to the patient during or after experiencing gastrointestinal ischemia-reperfusion, as in instant claim 23.
Boracelli et al. (Nitric oxide 2006, 14, 212-218, cited in IDS) teaches the selective inhibition of iNOS (as in instant claim 26) by administration of aminoguanidine prevents intestinal ischemia-reperfusion injury (Abstract).
Arya et al. (Brain Circulation 2018, 165-173) teaches the brain-gut axis after stroke. Arya teaches (figure 1) changes in the brain -gut-microbia axis after cerebral ischemic stroke, and the gut immune response to brain injury. Arya teaches (page 170, right column, second paragraph) that the GI tract contains >70% of inflammatory and immune cells in the body, and plays a key role in inflammatory and immune response after injury in remote organs including the brain. Arya teaches (page 170, right column, first paragraph) that the gut inflammatory and immune cells play a key role in the development of brain injury in cerebral stroke; migration of gut inflammatory and immune cells to the CNS may have a significant impact on the brain damage severity and duration after stroke.
Bedard teaches (page 279, left column, under point 2. Colon) NADPH oxidases, such as NOX1, NOX2, and Dual oxidase 2 (DUOX2), as ROS generating enzymes. These different NOX isoforms have tissue/cell selective expression: NOX2 expressed in the colon, NOX1 which is highly expressed in the colon, and DUOX2 which is expressed in the distal gastrointestinal tract, in particular cecum, colon. Bedard teaches the link between ROS generation, inflammation, immune defense.
It would have been obvious to combine the teachings of Danielisova, Boracelli and Arya, and Bedard to arrive at the instant invention.
The person of ordinary skill in the art would have been motivated to administer aminoguanidine to a patient suffering from cerebral ischemic stroke in the method taught by Danielisova, and monitor for inflammatory factors and expression of Nox2, Duox2 genes in the intestinal tissue, because
Danielisova teaches administering aminoguanidine to treat cerebral ischemic stroke;
Arya teaches changes in the brain -gut-microbia axis after cerebral ischemic stroke, the gut immune response to brain injury, and the fact that GI tract contains >70% of inflammatory and immune cells in the body, and plays a key role in inflammatory and immune response after brain injury in cerebral stroke; and
Bedard teaches NADPH oxidases, such as NOX1, NOX2, and Dual oxidase 2 (DUOX2), as ROS generating enzymes, expressed in gastrointestinal tract/ colon, and the link between ROS generation, inflammation, immune defense.
Thus, the person of ordinary skill in the art would have administered aminoguanidine to a person suffering from cerebral ischemic stroke in the method of Danielisova, and would have monitored the gastrointestinal expression of NOX1, NOX2, and Dual oxidase 2 (DUOX2) genes, as inflammation biomarkers in the colon, before and after treatment, with the expectation that cerebral stroke causes increased levels of inflammatory markers in the gastrointestinal tract (Arya), and treatment of the cerebral ischemic stroke with aminoguanidine (Danielisova) results in a decrease in said gastrointestinal inflammation biomarkers.
Further, since Boracelli teaches that aminoguanidine prevents/treats intestinal ischemia-reperfusion injury, the person of ordinary skill in the art would have administered aminoguanidine to a person suffering from cerebral ischemic stroke and GI ischemia reperfusion injury caused by cerebral ischemic stroke, with the expectation that aminoguanidine is effective to treat both cerebral ischemic stroke and GI ischemia reperfusion in said patient.
As such, claims 20, 23 are rejected as prima facie obvious.
Conclusion
Claims 20-21, 23, 26-29, 33, 35, 36 are rejected.
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 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.
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/IRINA NEAGU/Primary Examiner, Art Unit 1629
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