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
Response to Amendments
The amendments submitted 01/22/2026 have been entered.
Information Disclosure Statement
The IDS submitted entries submitted 04/17/2025 have been considered.
Restriction/Species Election
The election of the following species with traverse in the remarks submitted 04/17/2025 was acknowledged in the prior office action.
At the examiner’s discretion, search and examination was expanded to all possible additional components contained within claims 1-27 which are:
-lauryl lactate,
-capric triglyceride,
-benzyl alcohol,
-dimethyl isosorbide,
-muscle relaxant or cramping relief compounds (claims 14 and 15),
-sleep aids,
-anesthetic or analgesic compounds (claims 17-19).
Claim 28 remains withdrawn.
Status of Claims
Claims currently pending are claims 1 and 5-28.
Claims currently under examination are claims 1 and 5-27.
Withdrawn Objections and Rejections
In view of the amendments made, the objection made in the prior office action has been withdrawn.
In view of the amendments made, the 112(a) scope of enablement rejection and 112(b) made in the prior office action has been withdrawn.
Maintained Rejections
Claim Rejections - 35 USC § 103
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.
Claim(s) 1 and 5-27 is/are rejected under 35 U.S.C. 103 as being unpatentable over Fernyhough (US2017/0027957) in view of Lane (International Journal of pharmaceutics, 447, 2013, 12-21), Rodrigues (Expert Review of Dermatology, 7:4, 383-397, 2012), Cohen (Anesthesiology, 2004, 101:495-526), Slominski (Endocrine, vol. 27, no. 2, 137-147, 2005), Caldwell (Aviation, Space, and Environmental Medicine, vol. 71, No. 3, 2000), McAlvin (Focal Controlled Drug Delivery, Advances in Delivery Science and Technology, 2014, p. 653-677), and Bruni (Molecules, 2018, 23, 2478) and in view of Millipore-Sigma (BRIJ® 93 product page, url= https://www.sigmaaldrich.com/US/en/product/aldrich/388866, accessed 07/09/2025, specification sheet included).
Regarding claims 1, 11-12, and 22-23 Fernyhough on p. 2, para. [0009] teaches pirenzepine as a selective M1 receptor antagonist. Fernyhough throughout the reference and specifically at p. 9, para. [0092] contemplates a pharmaceutical composition comprising pirenzepine in a total weight percent between 0.1% to about 95%.
Fernyhough in Fig. 12 teaches a composition comprising pirenzepine and DMSO.
Regarding the dose amounts in claims 22-23, while Fernyhough contemplates weight percent of pirenzepine, one of ordinary skill in the art could easily reach the dose amounts from the weight percents via simple calculations. Additionally, the MPEP section 2144.05, subsection II states:
“The adjustment of particular conventional working conditions (e.g., determining result effective amounts of the ingredients beneficially taught by the cited references), is deemed merely a matter of judicious selection and routine optimization which is well within the purview of the skilled artisan. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical.
“[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.” In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). Accordingly, this type of modification would have been well within the purview of the skilled artisan and no more than an effort to optimize results.”
Fernyhough on p. 11, para. [0104] contemplates penetration enhancers including BRIJ® 93, and other BRIJ® products.
As evidenced by Millipore-Sigma, the structure of BRIJ® 93, shown below, is that of a polyethylene glycol alkyl ether.
BRIJ® 93
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See attached product specification sheet for additional details.
Regarding claim 7, Fernyhough on p. 12-13, para. [0113] contemplates capric triglyceride as an additional emollient.
Regarding claim 8, Fernyhough on p. 10, para. [0100] contemplates additional penetration enhancers including benzyl alcohol.
Regarding claim 10, Fernyhough on p. 2, para. [0010] contemplates salts of pirenzepine.
Regarding claim 13, Fernyhough on p. 9, para. [0096] contemplates hydrogels.
Regarding claim 21, Fernyhough on p. 12, para. [0112] contemplates formulations with viscosities greater than 1000 cps.
Regarding claim 26, Fernyhough on p. 9, para. [0089] states “This disclosure provides compositions comprising agents that include, but are not limited to…pirenzepine…and the like to treat peripheral neuropathy induced by diabetes.”
Regarding claim 27, Fernyhough on p. 6, para. [0071] contemplates Type 2 diabetes as a preferred embodiment of a peripheral neuropathy to be treated.
Fernyhough does not explicitly mention fatty acid esters, dimethyl isosorbide, muscle relaxants, sleep aid’s, anesthetics and/or analgesics. This is addressed by the combination of Lane, Rodrigues, Cohen, Slominski, Caldwell, McAlvin, and Bruni.
Regarding claims 5-6, Lane on p. 17, sec. 4.3.3 teaches lauryl lactate as a commercial product available for creams and patches. Considering that lauryl lactate has been reduced to a commercial product for creams, one of ordinary skill in the art would find it obvious to modify the composition of Fernyhough to include lauryl lactate.
Regarding claim 9, Rodrigues on p. 388, left col. para. 3 teaches dimethyl isosorbide as an example of a permeation enhancer. Considering the art identifies dimethyl isosorbide as a permeation enhancer, one of ordinary skill would find it obvious to include the compound within compositions similar to those taught in Fernyhough to enhance the permeability of Fernyhough’s compositions.
Regarding claims 14-15, Cohen on p. 512, sec. Magnesium teaches that magnesium is known to cause muscle relaxation in pharmacologic doses. Cohen also teaches that magnesium depletion causes neuromuscular excitability which leads to tremors and cramps. Fernyhough on p. 1, para. [0007] teaches that a symptom of neuropathy is “neuropathic pain such as inappropriate tingling, burning shooting, or aching sensations”. One of ordinary skill would find it obvious to include magnesium in the composition of Fernyhough considering that magnesium is known to treat muscle excitability (cramps, pain, etc.) which is a symptom of neuropathy.
Regarding claim 16, Slominski on p. 144, sec. Melatonin as a Topically Applied Drug in Dermatology teaches that melatonin can be incorporated into cream preparations and that “the skin may be an optimal organ not only for the treatment of local pathways with topical melatonin application, but also for the possibility of transdermal delivery…”
Caldwell on p. 241, sec. Melatonin as a Sleep-Promoting Substance teaches melatonin as a sleep aid where it states “Since melatonin’s sleep-inducing effects are most consistent with daytime administration…”.
Regarding claim 17-18, McAlvin on p. 654, para. 1 teaches amino-amide and amino-ester compounds as conventional local anesthetic that are commonly used in clinical practice. Considering that these compound classes are known in the art to be conventional anesthetics, one of ordinary skill would find it obvious to include said compounds in formulations for their anesthetic properties.
Regarding claim 19, Bruni in its abstracts suggests cannabinoids show a strong benefit for treating pain, inflammation, and other conditions. Bruni on p. 10 also discusses topical administration of cannabinoids. One of ordinary skill in the art would find it obvious to include a cannabinoid into the composition of Fernyhough to make use of the anti-inflammation and pain treatments properties.
Regarding claims 20 and 23-25, these claims are drawn to specific properties of the formulation. That is, the effect of having a drying time of about 30 seconds to about 30 minutes and the effect of the dose of pirenzepine being administered within about 18 hours to about 24 hours are properties of the formulation. These properties would be made obvious by any composition that embraces the claims as discussed above. Additionally, formulating a composition to have the properties above would be well within the skillset of one of ordinary skill in the art.
Response to Arguments
Applicant states that “the data in Fig. 12 show that pirenzepine-induced neurite outgrowth in cultured adult sensory neurons derived from rats was dose-dependently inhibited by the CaMKK inhibitor, STO-609. See Fernyhough at ¶[0137]. The sensory neurons in Fernyhough Fig. 12 were treated with 1 μM pirenzepine alone or with different concentrations of STO-609. The neurite outgrowth in these samples was compared to two controls, one of which included DMSO. Thus, it was only the control samples which included DMSO.”
Fig. 12 is shown below.
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Para. [0137] of Fernyhough states, fully, “The data in FIG. 12 show that pirenzepine-induced neurite outgrowth in cultured adult sensory neurons derived from rats was doe-dependently inhibited by the CaMKK inhibitor, STO-609 (data are means±SEM of N=8-10 replicate cultures. Significant differences were determined by oneway ANOVA followed by Dunnett’s post-hoc test.” While the paragraph not explicitly state that pirenzepine was combined with DMSO, as an excipient, it can at least be gleaned from figure 12, that DMSO was combined with pirenzepine. Even if DMSO was not combined with pirenzepine, DMSO’s usage as an excipient is clear in this figure and one of ordinary skill would be able to determine that pirenzepine can be combined with DMSO as an excipient. Essentially, DMSO efficacy as an excipient is well known within the art and Fernyhough displays this clearly.
Applicant then points to the unexpected result of combining DMSO and, specifically, Brij 78. The examiner acknowledges the significant improvement as shown in instant figure 2, Win41T, shown below.
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The Win41T composition is shown in table 2 of the instant specification.
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However, it is not clear if this improvement is an additive improvement or a synergistic improvement in view of the teachings of Buyuktimkin (WO2011112875).
Buyuktimkin in para. [0390]-[0448] teaches a number of studies that examined the effect of altering the various constituents of composition comprising Ibuprofen, DMSO, water, ethanol, propylene glycol. Glycerin, Brij30, cholesterol, SLS, sodium carbonate, SLES, and Brij 78. Buyuktimkin in para. [0433] teaches table 34, results summarized in para. [0434]-[0436].
Table 34
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Similarly, in para. [0417]-[0420] and Table 30, Buyuktimkin teaches the effect of altering Brij 78 levels within the same composition.
Table 30
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Buyuktimkin in para. [0420] states “A five- to nine-fold enhancement in the delivery of ibuprofen as compared to Ibugel was observed for the formulations tested. For formulations containing 0.2% cholesterol and SLES, increasing the Brij 78 concentration to 2% apparently decreased permeability of ibuprofen….For formulations containing 0.2% cholesterol and SLS, increasing the Brij 78 concentration to 2% seems to have no impact on the permeability of ibuprofen.” However, Buyuktimkin in para. [0338] teaches a table showing results of the addition of Brij 78, Increased Ethanol, and removing glycerin on the permeability of ibuprofen. Buyuktimkin in para. [0399] states “A two- to three fold increase in ibuprofen delivery compared to ibugel was achieved for all the formulations.
Table 25
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These tables at least show that adding Brij 78 to a composition would increase the permeability of a compound.
Notably, the addition and DMSO and Brij 78 significantly increased the permeability of ibuprofen compared to an Ibugel composition. This indicates that administering a compound with at least DMSO and Brij 78 would drastically increase the permeability of a compound.
The above teachings show that the combination of DMSO and Brij 78 can drastically increase permeability and/or flux across the skin. It is not clear from the available information whether the unexpected effective is simply an additive effect or if it is actually a synergistic effect.
Conclusion
No claims allowed.
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.
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/L.G./Examiner, Art Unit 1624
/SUSANNA MOORE/Primary Examiner, Art Unit 1624
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