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 .
Status of the claims
Pending claims 2-21 have been examined on the merits.
Withdrawn Grounds of Rejection
The rejection of claims 7-21 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ),
is withdrawn due to claim Amendment.
Maintained Rejection
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 (i.e., changing from AIA to pre-AIA ) 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 text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office
action.
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 2-9, 12-21 are rejected under 35 U.S.C. 103 as being unpatentable over
Fernyhough et al. (WO 2012/055018) in view of Melli et al. (Expert Opinion on Drug Discovery, 4:10(2009), 1035-1045).
Regarding claim 2, 14, 17, Fernyhough (abstract) teaches compositions for treating diabetic symmetrical polyneuropathy in a subject in need thereof. Fernyhough (page 1, lines 12-16) teaches “symmetrical polyneuropathy” “clinical symptoms may include ... loss of function of the nerves comprising the peripheral nervous system.” Fernyhough (page 50, claim 1; page 52, claim 11) also teaches “an effective amount of a muscarinic acetylcholine receptor antagonist and a pharmacologically acceptable carrier”) that comprise the muscarinic acetylcholine receptor antagonist, pirenzepine. Although Fernyhough (page 53, claim 16) teaches treating diabetic neuropathy, including diabetic sensory neuropathy, Fernyhough does not specifically teach treating chemotherapy-induced peripheral neuropathy (CIPN). Fernyhough (page 7, line 27 bridged page 8, line 1-4) further teaches that terms “"treatment,” “treating,” and similar terms encompass a range of effects, including both prophylactic (preventive) and therapeutic action.
However, Fernyhough (page 11, lines 23-25) specifically teaches that M1R antagonists are useful in “therapeutic compositions for distal symmetrical polyneuropathy and/or tactile allodynia” which is within the scope of the instant claims. In addition, Fernyhough (page 35-39, Examples 2-6) details substantial experimental data supporting the therapy through identifying neurite outgrowth in non-diabetic constructs. Thus, one of ordinary skill in the art had a reasonable expectation that the M1R antagonists would be effective in the neuropathies identified by Fernyhough. Furthermore, Fernyhough clearly teaches that muscarinic receptor antagonist modulate neuronal activity and reduce neuropathic pain, a symptom common to all forms of peripheral neuropathy. Although diabetic neuropathy is exemplified, the underlying mechanisms, nerve injury, altered neurotransmission, and inflammation which are shared across neuropathies. Thus, it would have been obvious to a person of ordinary skill in the art to expect similar therapeutic benefit for chemotherapy-induced peripheral neuropathy.
In addition, one of ordinary skill in the art would have considered Fernyhough’s teachings that the muscarinic acetylcholine receptor antagonist pirenzepine stimulates neurite outgrowth in an in vitro assay consisting of cultured excised adult and juvenile neurons from rats (page 34: Example 1: sensory neurons from DRG; Fig. 2; Fig. 3: effects of “muscarinic acetylcholine type 1 receptor (M1R) antagonists on neurite outgrowth from neurons cultured from normal rats” (page 3, line 26-28) and in mouse models with subcutaneous injections of pirenzepine (page 39: Example 7) in combination with the teaching of Melli that DRG neuron cultures provide a model for peripheral neuropathies caused by chemotherapeutic agents including paclitaxel (Melli Table 1: "Paclitaxel associated neuropathy"; p. 1035-36: "dorsal root ganglia (DRG) derived sensory neuron culture system as an excellent model in unveiling the pathogenic mechanisms of PNS"; p. 1040-43).
One of ordinary skill in the art would know from the teaching of Fernyhough that the
mechanism of action of M1R antagonists, including pirenzepine, accelerate axonal outgrowth in
peripheral neurons and would therefore be useful in treating peripheral neuropathy, including
CIPN as suggested by Melli through a similar model. This is further supported by Fernyhough's
experiments in "neurites from excised neurons from a normal rat" where the administration of
pirenzepine tripled the neurite outgrowth rate (page 33, Example 2) and a number of mouse
models of neuropathy including prophylactic and reversal effects from administering pirenzepine
(Example 7, 9-18). Such a result would suggest to one of ordinary skill in the art that antagonists such as pirenzepine would have utility in treating peripheral neuropathy even in CIPN cases. One of ordinary skill in the art would have a reasonable expectation of success because of the successful demonstration of increased neurite growth which is related to the underlying condition of peripheral neuropathy, even with non-diabetic causes.
One of ordinary skill in the art would consider routine and well within their technical grasp the process of utilizing a therapeutic agent shown to have positive effects in a related experimental demonstration. In addition, those of ordinary skill in the art routinely screen agents for therapeutic use in treating a condition shown to share a pathway related to the condition, such as taught by Melli (p. 1036). Therefore, it would be obvious to one of ordinary skill in the art to apply the combined teachings of Fernyhough and Melli and administer pirenzepine to subjects with CIPN and arrive at the claimed invention.
Regarding claims 2-6, wherein the composition comprises a non-ionic skin-penetration
enhancer for topical administration in an amount of 0.5%, Fernyhough teaches topical
administration (claim 3) including penetration enhancers such as dimethylsulfoxide (p. 22, line 4-25) in amount of “about 0.5%” (p. 26, line 3-9) such that one of ordinary skill in the art would have reasonably considered formulating the same topical composition and arrive at the claimed
invention.
Regarding claims 7-8, 19, Fernyhough (page 50, claims 4-5) teaches the same formulation that one of ordinary skill in the art would have reasonably considered and arrive at the claimed invention.
Regarding claims 9 and 12, 16, 18, Fernyhough (page 50, claim 8 bridged page 51; page 52, claim 11) specifically teaches pirenzepine and its derivatives.
Regarding claim 13, Fernyhough (p. 31, line 1-15) teaches the muscarinic acetylcholine receptor antagonist as “about 0.1 %” and “about 10%).”
Regarding claims 15-16, 20-21, one of ordinary skill in the art would have a reasonable expectation that a subject suffering from CIPN was also undergoing chemotherapy including those known to cause CIPN as taught by Melli (Table 1: "Paclitaxel associated neuropathy") and arrive at the claimed invention.
Claims 10-11 are rejected under 35 U.S.C. 103 as being unpatentable over
Fernyhough et al. (WO 2012/055018)
Regarding claim 10, Fernyhough (page 51, claim 9) and as applied to claims 2-9 above, teaches identical chemical structure as in Formula I:
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754
684
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Regarding claim 11, Fernyhough (page 52, claim 10) teaches identical chemical structure as in Formula II:
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704
676
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The instant claims would have been obvious to a person of ordinary skill in the art because Fernyhough explicitly teaches the same chemical structure, thus, there is no distinction them. Therefore, a person of ordinary skill in the art would reasonably expect any compound derived from the chemical structure to possess the same properties and uses as those taught by Fernyhough.
Maintained Rejection
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine
grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or
improper timewise extension of the "right to exclude" granted by a patent and to prevent
possible harassment by multiple assignees. A nonstatutory double patenting rejection is
appropriate where the conflicting claims are not identical, but at least one examined application
claim is not patentably distinct from the reference claim(s) because the examined application
claim is either anticipated by, or would have been obvious over, the reference claim(s). See,
e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d
1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Langi, 759 F.2d 887,225 USPQ 645 (Fed. Cir.
1985); In re Van Ornum, 686 F.2d 937,214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d
438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA
1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321 (c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting
provided the reference application or patent either is shown to be commonly owned with the
examined application, or claims an invention made as a result of activities undertaken within the
scope of a joint research agreement. See MPEP § 717.02 for applications subject to
examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159.
See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to
file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR
1.321 (b).
The USPTO Internet website contains terminal disclaimer forms which may be used.
Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the
form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 2-7, 9-12, 16-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7 of U.S. Patent No. 10307428 in view of Fernyhough et al. (WO 2012/055018) in view of Melli et al. (Expert Opinion on Drug Discovery, 4:10 (2009), 1035-1045).
Although the claims at issue are not identical, they are not patentably distinct from each
other because compounds claimed in US patent '428 are comparable to those of the instant
claims.
Both the instant claims in the US patent '428 teach the same compound for different formulation and/or for different applications. Thus, the claims are not patentably distinct and the use of the same compound in different formulations or application does not render the instant claims non-obvious. Because, a POSITA would recognize that the use of the same compound in a different but obvious formulation does not create a patentably distinct invention. Thus, issue an allowance would effectively extend the patent protection for the same invention beyond the statutory term.
Claims 1-7 of the US patent '428 teach a topical composition for use in therapy of diabetic symmetrical polyneuropathy by administering a composition comprising
an effective amount of pirenzepine; and; optionally formulated for topical, lotion, cream or gel, and including skin penetration enhancer at a concentration of at least 0.5 % by weight, reading on the instant claims 2-7, 9-12, 16-19. While the instant claim teaches a method for treating a chemotherapy-induced peripheral neuropathy (CIPN) by topically administering a composition comprising a muscarinic acetylcholine receptor antagonist, including but not limited to Pirenzepine, and a pharmacologically acceptable carrier and/or skin penetration enhancer.
It is evident that the composition discloses in both US patent '428 and instant claim are substantially identical in their formulation and active ingredient, and carrier system. While US patent '428 teaches does not explicitly teach CIPN, however, because pirenzepine, modulates neurotropic signaling pathways and affects neuronal growth, this clearly indicate a treatment applicable to neuropathy-related pathologies beyond diabetes, and which would involve CIPN because of the shared neuronal degeneration mechanism. Therefore, it would have ben obvious to a POSITA to apply the topical pirenzepine composition of the US patent '428 to other neuropathic conditions, including CIPN, to arrive at the claimed invention. Moreover, it is evident that the main difference between US patent '428 and the instant claim is on disease indication (diabetic vs CPN), which does not render the claims patentably distinct, because both involves the treatment composition and neuropathic disease.
Given that the claimed compounds of the instant claim are similar to that of the US patent ‘428 in view of Melli, without meaningful inventive distinction, thus the instant application is not in proper condition to warrant a Notice of Allowance. This is because, allowing both claims to issue as separate patents would unjustly extend the patent rights beyond the statutory term.
Claims 2-7, 9-12, 16-19 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-1, 18-27 of U.S. Patent No. US 11,925,649
in view of Femyhough et al. (WO 2012/055018) in view of Melli et al. (Expert
Opinion on Drug Discovery, 4:10 (2009), 1035-1045).
Although the claims at issue are not identical, they are not patentably distinct from each
other because compounds claimed in US patent '649 are comparable to those of the instant
claims.
Claims 1-12 and 18-27 of the US patent '649 teaches a method of treating diabetic peripheral neuropathy by administering a composition comprising an effective amount of a selective muscarinic acetylcholine M1 receptor antagonist, such as, pirenzepine, telenzepine, atropine, oxybutynin or other selective for the M1 receptors; optionally formulated for topical, lotion, cream or gel, and including skin penetration enhancer at a concentration of at least 0.1 % by weight. oral, reading on the instant claim 2-7, 9-12, 16-19.
The instant claims teach a method While the instant claim teaches a method for treating a chemotherapy-induced peripheral neuropathy (CIPN) by topically administering a composition comprising a muscarinic acetylcholine receptor antagonist, including but not limited to Pirenzepine, and a pharmacologically acceptable carrier and/or skin penetration enhancer,
While the instant claim teaches a method for treating a chemotherapy-induced peripheral neuropathy (CIPN) by topically administering a composition comprising a muscarinic acetylcholine receptor antagonist, including but not limited to Pirenzepine, and a pharmacologically acceptable carrier and/or skin penetration enhancer. Thus, it would have been obvious to a POSITA to apply the same pirenzepine-containing topical formulation disclosed in the US patent’649 to treat CIPN, a condition with the same underlying neuropathic mechanisms. Thus, it is evident that the instant claims are not patentably distinct over the US patent’649. For this reason, the modification in therapeutic target, from diabetic neuropathy to CIPN, clearly represents an obvious variation in intended us, which does not render the claims distinct to overcome double-patenting. Therefore, the double-patenting rejection is maintained.
Response to Argument
Applicant argues that Fernyhough does not teach or suggest that a topically applied muscarinic acetylcholine receptor M1 antagonist would be effective for treating chemotherapy-induced peripheral neuropathy (CIPN), or that a treatment for diabetic neuropathy would be applicable to neuropathies of other causes. Applicant’s argument is not persuasive, because
Fernyhough clearly teaches that muscarinic receptor antagonists can modulate neuronal activity and improve neuropathic pain, which would also apply to other form of neuropathic pain; because of the shared pathway across diverse forms of peripheral neuropathy irrespective of the underlying condition or cause. Thus, while Fernyhough specifically discusses diabetic neuropathy, however, the underlying mechanism of peripheral neuropathy, such as nerve injury, disrupted neurotransmission, and inflamed processes are also found in CIPN, not just diabetes. Therefore, it would have been obvious to a person of ordinary skill in the art (POSITA) to expect that a muscarinic receptor antagonist, including an M1 antagonist, including but not limited to pirenzepine, would offer therapeutic benefit in other type of peripheral neuropathy, such as CIPN. As evidence by Andrew discloses “M1R antagonist pirenzepine can prevent the neuropathy induced by chemotherapeutic agent.” (https://grantome.com/grant/NIH/R41-CA213555-01A1, Retrieved 11/10/2025).
Applicant argues that Melli is a review article on diabetic neuropathy and does not disclose or suggest treatments for CIPN. Also, Melli itself acknowledges that mechanism of chemotherapeutic neurotoxicity remains unclear and no effective treatments exists, confirming the absence of any teaching regarding M1 antagonists or their topical use. Applicant’s argument is not persuasive, because, while Melli is a review article, it nevertheless provides relevant background information regarding the mechanisms and pathway involved in peripheral neuropathies, including those induced by diabetes and chemotherapy or possibly other underlying conditions. These similarities would have suggested to a POSITA that agent modulating neuronal activity, such as muscarinic receptor antagonist, could be effective across different neuropathic conditions. Moreover, the statement “no effective regenerative or protective treatment has been found” does not refute the Melli relevance as a reference, but rather highlights the motivation for a POSITA to explore known neuromodulator compounds, such as muscarinic receptor antagonist or pirenzepine, for treating CIPN and diabetic neuropathy. Furthermore, although Melli does not explicitly disclose M1 antagonists or their topical application, the shared neurophysiological mechanism underlying peripheral neuropathies would have provided a reasonable expectation of success in employing such agents to treat CIPN. As evidence by Andrew discloses “M1R antagonist pirenzepine can prevent the neuropathy induced by chemotherapeutic agent.” (https://grantome.com/grant/NIH/R41-CA213555-01A1, Retrieved 11/10/2025).
Applicant further argues that neither Fernyhough nor Melli suggests modifying Fernyhough to arrive at the claimed invention. This is because diabetic neuropathy and CIPN arise from different mechanisms, therefore, there would be no reasonable expectation that a treatment effective for diabetic neuropathy would also be effective for CIPN. Applicant’s argument is not persuasive because, while the specific causes of diabetic neuropathy and CIPN differ, both conditions involve common downstream pathological processes in peripheral nerves, such as neuronal hyperexcitability, inflammation, and altered neurotransmission within the dorsal root ganglia. Fernyhough teaches that muscarinic acetylcholine receptor antagonists, including M1 antagonists or pirenzepine, modulate neuronal signaling and reduce neuropathic pain, such mechanism not limited to any particular diagnosis. Melli further emphasizes that peripheral neuropathies share similar cellular targets and pathways, supporting the rationale that therapies acting on this shared mechanism could be effective across different neuropathic conditions. Contrary to Applicant, it would have been obvious to a POSITA to recognize other forms of neuropathy, such as CIPN, and modify Fernyhough’s teachings in view of Melli with a reasonable expectation of success based on the shared neurological features.
Applicant also argues that US patent '428 fails to teach a method of treating CIPN. Applicant’s argument is not persuasive, because a nonstatutory double patenting is primarily based on whether a claimed a subject matter is patentably distinct from an earlier patent. Therefore, a nonstatutory double patenting is warranted even when subject matter is to a different disease indication, if the underlying utility and therapeutic composition are substantially similar, which is the case here. Therefore, the double-patenting rejection is maintained.
Conclusion
Therefore, claims 2-21 are rejected.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PIERRE PAUL ELENISTE whose telephone number is (571)270-0589. The examiner can normally be reached Monday - Friday 8:00 am - 5:00 pm (EST).
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/P.P.E./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622