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 .
Claims 2, 5, 6, 10 have been canceled. Claims 1, 3, 4, 7-9 remain pending.
Election/Restrictions
Applicants elected Group I, claims 1-6, without traverse in the reply filed on 10-24-25. Claims 7-9 remain withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim.
Claims 1, 2, 4 remain under consideration.
Claim Rejections - 35 USC § 112
The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease.
The features of the ligation in claim 1 should all be together.
The features of administering the NO inhibitor in claim 1 should all be together.
The steps in claim 1 should be clear, positive, active steps, e.g. “permanently ligating…”, “administering…”.
The active steps never require clamping the CCA of a non-human mammal.
The active steps never require administering an NO inhibitor to a non-human mammal.
The body of the claim further limits the “cerebrovascular disease” in the preamble without saying the clamping and administering the NO inhibitor results in palsy, stroke, cerebral hemorrhage, or vascular dementia.
Claim 1 can be written more clearly and concisely as ---A method of making a non-human mammal that has palsy, a stroke, cerebral hemorrhage, or vascular dementia, the method comprising:
permanently ligating the common carotid artery of a non-human mammal and administering 100-400 mg/kg of an nitric oxide inhibitor immediately before or after the ligating such that the non-human mammal has palsy, a stroke, cerebral hemorrhage, or vascular dementia---.
Claim Rejections - 35 USC § 112
Enablement
Claims 1, 3, 4 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 ligating a common carotid artery in a non-human mammal and administering an inhibitor of nitric oxide such that cerebral ischemia occurs, does not reasonably provide enablement for obtaining a non-human mammal that has palsy, stroke, cerebral hemorrhage, or vascular dementia as broadly encompassed by claim 1. 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/use the invention commensurate in scope with these claims.
The specification does not enable making/using a non-human mammal with palsy, stroke, cerebral hemorrhage, or vascular dementia as broadly encompassed by claim 1 other than permanently clamping the CCA in a non-human mammal and administering an inhibitor of NO to the mammal such that cerebral ischemia occurs. The specification does not enable obtaining a model of palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. While the preamble of claim 1 says it’s a method of making a model of cerebrovascular disease, the body of the requires performing the steps and obtaining palsy, stroke, cerebral hemorrhage, or vascular dementia. The body of the claim further limits the “cerebrovascular disease” in the preamble without saying the clamping and administering the NO inhibitor results in palsy, stroke, cerebral hemorrhage, or vascular dementia. The specification is limited to performing the active steps such that cerebral ischemia is obtained (Examples). The specification does not correlate cerebral ischemia to obtaining palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. Palsy affects the facial nerve, but applicants did not achieve this using the method steps claimed. Cerebral hemorrhage is a rupture of a blood vessel in the skull, but applicants did not achieve this using the method steps claimed. Cerebral dementia causes thinking and memory problems, but applicants did not achieve this using the method steps claimed. Given the lack of guidance in the specification taken with the art at the time of filing, it would have required those of skill undue experimentation to determine how to make/use the method of claim 1 as broadly claimed other than clamping the CCA in a non-human mammal and administering an inhibitor of NO to the mammal such that cerebral ischemia occurs.
Response to argument
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Written Description
Claims 1, 3, 4 remain rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
The specification lacks written description for a non-human mammal with palsy, stroke, cerebral hemorrhage, or vascular dementia as broadly encompassed by claim 1 other than permanently clamping the CCA in a non-human mammal and administering an inhibitor of NO to the mammal such that cerebral ischemia occurs. The specification does not enable obtaining a model of palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. While the preamble of claim 1 says it’s a method of making a model of cerebrovascular disease, the body of the requires performing the steps and obtaining palsy, stroke, cerebral hemorrhage, or vascular dementia. The body of the claim further limits the “cerebrovascular disease” in the preamble without saying the clamping and administering the NO inhibitor results in palsy, stroke, cerebral hemorrhage, or vascular dementia. The specification is limited to performing the active steps such that cerebral ischemia is obtained (Examples). The specification does not correlate cerebral ischemia to obtaining palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. Palsy affects the facial nerve, but applicants did not achieve this using the method steps claimed. Cerebral hemorrhage is a rupture of a blood vessel in the skull, but applicants did not achieve this using the method steps claimed. Cerebral dementia causes thinking and memory problems, but applicants did not achieve this using the method steps claimed. Accordingly, the specification lacks written description for the method of claim 1 as broadly claimed other than clamping the CCA in a non-human mammal and administering an inhibitor of NO to the mammal such that cerebral ischemia occurs.
Response to argument
Applicants argue the amendment overcomes the rejection. Applicants’ argument is not persuasive for reasons set forth above.
Indefiniteness
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 1, 3, 4 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.
The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. It also doesn’t make sense because the mammal is given anesthesia and undergoes numerous other steps beyond clamping and administering an NO inhibitor.
The metes and bounds of administering an NO inhibitor “immediately” before or after permanently ligating the CAA as newly require in claim 1 cannot be determined. It is unclear whether minutes or hours (or days) may go by or if the phrase is limited to seconds. If the phrase is limited to seconds, it is unclear how many seconds are considered “immediate”. Therefore, those of skill would not be able to determine when they were infringing on the claim.
The phrase “nitric oxide synthase (NOS) inhibitor” in claim 3 lacks antecedent basis. Claim 1 is limited to an “nitric oxide (NO) inhibitor”.
Claim Rejections - 35 USC § 102
Withdrawn rejection
The rejection of claims 1, 3, 4 under 35 U.S.C. 102a1 as being anticipated by Yata (CA2155627). Yata taught ligating the carotid artery of a mouse while administering nitric oxide synthase inhibitor (pg 108-109, Test 4). This causes cerebral ischemia which makes it a model of cerebrovascular disease as required in claim 1. Yata did not teach permanent ligation as newly required in claim 1 (formerly in claim 2 – now canceled).
The rejection of claims 1, 3, 4 under 35 U.S.C. 102a1 as being anticipated by Ladipo (Nigerian J. Health Biomed. Sci., 2006, Vol. 5, No. 2) has been withdrawn. Ladipo performed bilateral carotid artery occlusion in a rat and administered L-NAME (abstract). Bilateral carotid artery occlusion is equivalent to occluding the common carotid artery. This makes the rat of Ladipo a model of cerebrovascular disease as required in claim 1 because the steps are exactly the same as those described by applicants as being part of the invention. However, Ladipo did not teach permanently ligating the CAA as newly required in claim 1 (formerly in claim 2 – now canceled).
The rejection of claims 1, 3, 4 under 35 U.S.C. 102a1 as being anticipated by Aguilar-Alonso (Brain Res., 2008, Vol. 1200, pg 89-98) has been withdrawn. Aguilar-Alonso occluded the common carotid artery occlusion in a rat and administered nitro-arginine methyl ester 1 hour beforehand (abstract). This makes the rat of Aguilar-Alonso a model of cerebrovascular disease as required in claim 1 because the steps are exactly the same as those described by applicants as being part of the invention. However, Alonso did not teach permanently ligating the CAA as newly required in claim 1 (formerly in claim 2 – now canceled).
The rejection of claims 1, 3-6 under 35 U.S.C. 102a1 as being anticipated by Horie (J. Neurosci. Methods, 2008, Vol. 173, pg 286-290) has been withdrawn. Horie occluded the common carotid artery occlusion in a rat and administered NAME (abstract). Horie administered the nitro-arginine methyl ester immediately before the artery was ligated as required in claim 1 (Materials and Methods). The active steps of Horie are EXACTLY the same as those claimed and described by applicants as being part of the invention. Therefore, the active steps of Horie inherently MUST result in palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. However, Horie did not teach permanently ligating the CAA as newly required in claim 1 (formerly in claim 2 – now canceled).
Pending rejections
A) Claims 1, 3, 4 remain rejected under 35 U.S.C. 102a1 as being anticipated by Cooke (WO 0074701).
Cooke taught ligating the common carotid artery (pg 23, line 15-19) and administering nitric oxide synthase inhibitor (L-NNMA; pg 5, lines 33-35; pg 11, line 28; pg 22, line 21; Fig. 7). This is an ex vivo animal model (pg 21, line 21) of cerebrovascular disease because it involves the permanently ligating the carotid artery as required in claim 2.
Cooke taught permanently ligating the carotid artery (pg 23, lines 15-19) as required in claim 1.
Cook administered the NOS inhibitor immediately after the artery was ligated as encompassed by claim 1 (pg 5, 11, 22 cited above).
The common carotid artery of Cook is an ex vivo model of palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1 because it contributes blood flow to the brain.
The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. It also doesn’t make sense because the mammal is given anesthesia and undergoes numerous other steps beyond clamping and administering an NO inhibitor. Therefore, Cooke taught a method “consisting essentially of” permanently clamping a CAA and immediately administering an inhibitor of NO as required in claim 1.
Cooke taught L-monomethyl-L-arginine (L-NNMA) as required in claim 3.
Cooke administered the NNMA intravenously as encompassed by claim 4 (pg 5, lines 33-35; pg 11, line 28; pg 22, line 21; Fig. 7) because it was put into medium that went through the artery.
Response to argument
Please separate arguments for each rejection because the issues for each are different.
Applicants discuss the prior art and claims and a “discovery” (pg 4). Applicants’ discussion is not an argument and is not persuasive for reasons set forth above.
Applicants argue Cooke did not teach a method “consisting essentially of” ligating a CAA and administering an inhibitor of NO as newly required in claim 1 (pg 5). Applicants’ argument is not persuasive. The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. Therefore, Cooke taught a method “consisting essentially of” permanently clamping a CAA and immediately administering an inhibitor of NO as required in claim 1.
B) Claims 1, 3, 4 remain rejected under 35 U.S.C. 102a1 as being anticipated by Bucala (5700447).
Bucala taught “both common carotid arteries were exposed and the right was ligated”. “Within 5 minutes of severing the artery, the left common carotid artery was temporarily occluded for 30 minutes or 1 hour” (col. 30, lines 30-45). “In some animals, aminoguanidine [ ] was given” (col. 30, lines 60-61). This is equivalent to the active step of claim 1. This causes cerebral ischemia and stroke (see the rest of Example 10) which makes it a model of cerebrovascular disease as required in claim 1.
Bucala removed the brains 24 hours later which is permanent ligation of the common carotid artery as required in claim 1.
Bucala administered the aminoguanidine before the artery was ligated (col. 30, line 59) which is “immediately before” as required in claim 1.
Bucala caused cerebral ischemia which is a palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1.
The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. It also doesn’t make sense because the mammal is given anesthesia and undergoes numerous other steps beyond clamping and administering an NO inhibitor. Therefore, Bucala taught a method “consisting essentially of” permanently clamping a CAA and immediately administering an inhibitor of NO as required in claim 1.
Bucala used aminoguanidine as required in claim 3.
Bucala administered the aminoguanidine intravenously (col. 30, line 61) as encompassed by claim 4.
Response to arguments
Applicants seem to argue Bucala is limited to using advanced glycosylation endproducts (pg 6) which is not “essentially” clamping and administering an NO inhibitor. Applicants’ argument is not persuasive. The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. It also doesn’t make sense because the mammal is given anesthesia and undergoes numerous other steps beyond clamping and administering an NO inhibitor. Therefore, Cooke taught a method “consisting essentially of” permanently clamping a CAA and immediately administering an inhibitor of NO as required in claim 1.
C) Claims 1 and 4 remain rejected under 35 U.S.C. 102a1 as being anticipated by Mazur (RU2532394).
Mazur taught permanently occluding the common carotid artery in a rat and administering ONMK, L-arginine, or Hypertryl (para 16 and 17). This causes cerebral vascular disease (para 3) which makes it a model of cerebrovascular disease as required in claim 1.
Mazur administered the aminoguanidine immediately before the artery was ligated as required in claim 1 (col. 30, line 59).
The active steps of Mazur are EXACTLY the same as those claimed and described by applicants as being part of the invention. Therefore, the active steps of Mazur inherently MUST result in palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1.
The phrase “consisting essentially of” in claim 1 does not make sense because it excludes any time after the ligating and administering a NO inhibitor where the non-human mammal develops any cerebrovascular disease. It also doesn’t make sense because the mammal is given anesthesia and undergoes numerous other steps beyond clamping and administering an NO inhibitor. Therefore, Mazur taught a method “consisting essentially of” permanently clamping a CAA and immediately administering an inhibitor of NO as required in claim 1.
Mazur administered the aminoguanidine intravenously (col. 30, line 61) as encompassed by claim 4.
Response to arguments
Applicants argue Mazur did not obtain palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1. Applicants’ argument is not persuasive because the active steps of Mazur are EXACTLY the same as those claimed and described by applicants as being part of the invention. Therefore, the active steps of Mazur inherently MUST result in palsy, stroke, cerebral hemorrhage, or vascular dementia as required in claim 1.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure:
Valazquez (WO 2018204475) taught ligating an artery of a mouse (para 17, 20, 21, 27, 28, 79, 84-87, 95, 96, 110) while administering nitric oxide synthase inhibitor (nitro L-arginine methyl ester (NAME)) (para 79, 83, 84, 95, 110). Valazquez taught ligating an artery while administering nitric oxide synthase inhibitor (para 85)
No claim is allowed.
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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Michael C. Wilson
/MICHAEL C WILSON/
Primary Examiner, Art Unit 1638
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