DETAILED ACTION
This office action is in response to the Applicant’s filing dated November 10th, 2025.
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 Claims
Claims 35-39, 41-46, 49-51 and 56-65 are pending in the instant application. Acknowledgement is made of Applicant's remarks and amendments filed on November 10th, 2025. Acknowledgement is made of Applicant's amendment of claims 35, 37-39, 41-42, 45, 50, 57 and 61-62; cancelation of claim 55; and addition of new claim 65.
Priority
This application is a 371 of PCT/US2021/012737 filed on January 8th, 2021; and a PRO of 62/959594 filed on January 10th, 2020.
Objections and/or Rejections and Response to Arguments
Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated (Maintained Objections and/or Rejections) or newly applied (New Objections and/or Rejections, Necessitated by Amendment or New Objections and/or Rejections, NOT Necessitated by Amendment). They constitute the complete set presently being applied to the instant application.
New Objections and/or Rejections
Necessitated by Claim Amendment
Claim Rejections - 35 USC § 112(b)
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.
Claim 62 is 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 62 is rejected on the basis that it contains improper Markush format. See MPEP §
2173.05(h). The Markush language recited “selected from the group consisting of minoxidil, finasteride SADBE, DPCP or combinations thereof” is improper; and should read “selected from the group consisting of minoxidil, finasteride SADBE, DPCP and combinations thereof”.
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 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 35-39, 41-42 and 65 are rejected under 35 U.S.C. 103 as being unpatentable over Freyschmidt-Paul et al (Journal of Investigative Dermatology. (1999), 113(1), 61-68), cited in a previous Office action; in view of Meanwell (Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. Journal of Medicinal Chemistry; 2018, 61 (14), 5822-5880), cited in a previous Office action.
Regarding claims 35-39, 41-42 and 65, Freyschmidt-Paul teaches the application of a therapeutically effective amount of SADBE in acetone (an organic solvent carrier), topically applied weekly to C3H/HeJ mice as a method of treating alopecia areata like hair loss (page 62, left column, paragraphs 2-4). C3H/HeJ mice spontaneously develop alopecia areata like hair loss with age (page 61, right column, last paragraph; page 62, left column, first paragraph) and are a well-established animal model of alopecia areata like hair loss, including forms like alopecia totalis and alopecia universalis. Although the mice themselves do not have a diagnosed autoimmune disorder, this mouse model provides a way to study the hair loss mechanisms and pathological features of alopecia areata hair loss. Freyschmidt-Paul discloses that unilateral hair regrowth occurred after SADBE treatment (page 63, left column, first paragraph).
Freyschmidt-Paul does not teach a method of treating alopecia like hair loss comprising administering the instantly claimed compound of Formula (1).
Meanwell teaches “Replacing hydrogen atoms with fluorine has been explored extensively in drug design, most commonly to replace those bound to an aromatic ring or in the context of a CF3 for CH3 (page 5823, left column, last paragraph). Because the introduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing the poor pharmacokinetic performance of compounds in vitro and in vivo” (page 5824, left column, second paragraph).
It would have been prima facie obvious to a person of ordinary skill in the art to substitute SADBE in the disclosed method of Freyschmidt-Paul with the instantly claimed compound of Formula (1), because SADBE has been shown as effective in treating hair loss and alopecia, and the compound of Formula (1) retains the same squaric acid core and alkyl substitution pattern while incorporating routine terminal CF3 for CH3 substitutions that Meanwell teaches have been explored extensively in drug design where these substitutions can modulate potency or interfere with metabolic modification (page 5823, left column, last paragraph). One of ordinary skill in the art would have had a reasonable expectation of success in at least maintaining baseline performance with the possibility of a more pronounced therapeutic response.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all of this would result in the methods of instant claims 35-39, 41-42 and 65 with a reasonable expectation of success.
Claims 43-46, 49-51 and 56-57 are rejected under 35 U.S.C. 103 as being unpatentable over Freyschmidt-Paul et al (Journal of Investigative Dermatology. (1999), 113(1), 61-68), cited in a previous Office action; in view of Meanwell (Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. Journal of Medicinal Chemistry; 2018, 61 (14), 5822-5880), cited in a previous Office action; further in view of Barman et al (US 2014/0079686 A1), cited in a previous Office action.
Regarding claims 43-46 and 49-51, Freyschmidt-Paul and Meanwell render obvious the method comprising administering the compound of Formula (1) as described in the above rejection.
Freyschmidt-Paul and Meanwell do not teach a method of treating alopecia like hair loss wherein the formulation further comprises alcoholic or aqueous carrier fluid, additional agents (e.g. minoxidil, finasteride or DPCP), desensitizers or steroids; nor that hair growth is increased by 10%, 15% or 20%.
Barman teaches methods of treating baldness, enhancing, stimulating or increasing hair growth or enhancing or increasing the thickness of hair on an area of skin of a human subject, with a hair growth promoting agent (pages 13 and 26, paragraphs [0240, 0352, 0357]). Barman teaches the hair growth promoting agent (pharmaceutical composition) is “selected from the group consisting of” one or more of the following in a list that includes SADBE and diphenyl cyclopropenone [DPCP] (sensitizers to cause inflammation); triamcinolone acetonide (glucocorticoid); minoxidil and finasteride (page 26, paragraph [0352]; page 95, claims 1 and 3). Barman further teaches the pharmaceutical composition further comprises water or ethanol as appropriate vehicles or carriers (page 31, paragraph [0401]). Barman teaches that anesthetic compounds (to decrease sensitivity) may also be administered topically, including lidocaine (page 30, paragraph [0394]). The aforementioned hair growth promoting agent is taught to increase hair growth by at least 10%, 15% or 20% (page 62, paragraph [0847]).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
It would have been prima facie obvious to a person of ordinary skill in the art to further formulate the method of Freyschmidt-Paul, as modified in view of Meanwell, with additional hair growth promoting agents, carriers, desensitizers or steroids as taught by Barman, because Barman teaches that such agents are conventionally combined in topical compositions for the treatment of hair loss and baldness, including alopecia related conditions, to enhance or stimulate hair growth. One of ordinary skill in the art would therefore have a reasonable expectation that incorporating the additional agents or carriers taught by Barman into the topical treatment method of Freyschmidt-Paul, as modified in view of Meanwell, would at least maintain baseline therapeutic efficacy, with the possibility of additive or enhanced hair growth response.
"It is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from their having been individually taught in the prior art." In re Kerkhoven, 626 F.2d 846, 850, 205 USPQ 1069, 1072 (CCPA 1980).
Regarding claims 56-57, Freyschmidt-Paul, Meanwell and Barman render obvious the method comprising administering the compound of Formula (1) as described in the above rejection.
Barman further teaches the subjects treated by the aforementioned method may have a disease or disorder including balding or hair loss including androgenetic alopecia, anagen effluvium and telogen effluvium (page 57, paragraphs [0745, 0747-0749]).
Taken together, all of this would result in the methods of instant claims 43-46, 49-51 and 56-57 with a reasonable expectation of success.
Maintained Objections and/or Rejections
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 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 58-64 are rejected under 35 U.S.C. 103 as being unpatentable over Freyschmidt-Paul et al (Journal of Investigative Dermatology. (1999), 113(1), 61-68), cited in a previous Office action; in view of Meanwell (Fluorine and Fluorinated Motifs in the Design and Application of Bioisosteres for Drug Design. Journal of Medicinal Chemistry; 2018, 61 (14), 5822-5880), cited in a previous Office action; further in view of Barman et al (US 2014/0079686 A1), cited in a previous Office action.
Regarding claims 58-64, Freyschmidt-Paul teaches a method of stimulating or increasing hair growth in C3H/HeJ mice with alopecia areata like hair loss, comprising administering a therapeutically effective amount of SADBE (page 62, left column, paragraphs 2-4).
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SADBE exhibits a high degree of structural similarity as that of the instantly claimed compound of Formula (I). The differences from SADBE to the instantly claimed compound of Formula (I) being:
The CH3 functional group terminating each alkyl chain have been targeted for routine structural modification, being replaced with a CF3 functional group.
Freyschmidt-Paul does not teach a SADBE with modified CF3 functional groups terminating the alkyl chains as seen in instant claim 58; or a pharmaceutical composition comprising the compound of Formula (I) and SADBE to stimulate or increase hair growth in a subject, wherein the subject does not have an autoimmune disease or have hair loss associated with an autoimmune disease.
Meanwell teaches “Replacing hydrogen atoms with fluorine has been explored extensively in drug design, most commonly to replace those bound to an aromatic ring or in the context of a CF3 for CH3 (page 5823, left column, last paragraph). Because the introduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing the poor pharmacokinetic performance of compounds in vitro and in vivo” (page 5824, left column, second paragraph).
MPEP 2144.09 states:
A prima facie case of obviousness may be made when chemical compounds have very close structural similarities and similar utilities. "An obviousness rejection based on similarity in chemical structure and function entails the motivation of one skilled in the art to make a claimed compound, in the expectation that compounds similar in structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245, 254 (CCPA 1979).
It would have been prima facie obvious to a person of ordinary skill in the art to routinely modify the structure of SADBE of Freyschmidt-Paul; particularly in light of the fact that SADBE has been shown as useful in treating hair loss and alopecia, and incorporate the teachings of Meanwell to reduce oxidative metabolism and optimize pharmacokinetic performance.
Structural modification of terminal functional groups, such as the methyl groups at the end of alkyl chains, is a well-established strategy in lead optimization, particularly when refining an already effective core scaffold. Bioisosteric replacements, such as the substitution of the terminal CH3 in each alkyl chain with CF3 as in the instant claims, are routinely employed in medicinal chemistry to fine tune pharmacodynamic and pharmacokinetic properties without materially altering the compound’s biological activity or overall function.
Barman teaches a pharmaceutical composition (hair growth promoting agent) that is “selected from the group consisting of” one or more of the following in a list that includes SADBE; triamcinolone acetonide (glucocorticoid); and minoxidil, finasteride, and diphenyl cyclopropenone [DPCP] (page 26, paragraph [0352]; page 95, claims 1 and 3). Barman further teaches the pharmaceutical composition further comprises water or ethanol as appropriate vehicles or carriers (page 31, paragraph [0401]); Barman teaches suitable dosage forms comprise solutions, suspensions, creams, gels, ointments, lotions, foams, aerosols, sprays, sticks, bars, shampoos or other hair products (page 32, [0408]).
SADBE is known in the art to stimulate or increase hair growth, and CF3 terminated alkyl chains are recognized bioisosteric modifications to enhance pharmacokinetic properties. Accordingly, it would have been prima facie obvious to a person of ordinary skill in the art to formulate a pharmaceutical composition comprising SADBE, as taught by Barman, and the modified compound of Formula (I), as made obvious by Freyschmidt-Paul and Meanwell. The expectation would be to improve pharmacokinetic performance while maintaining the baseline therapeutic effect. Absent evidence of unexpected results, these changes constitute predictable optimizations within the skill of an ordinary artisan.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all of this would have rendered the compound and composition of instant claims 58-64 prima facie obvious to a person of ordinary skill in the art, with a reasonable expectation of success.
Applicant argues:
Applicant contends that Freyschmidt-Paul does not provide motivation to modify SADBE to arrive at the compound of Formula (1). Meanwell is a review of fluorination of compounds developed by medicinal chemists; and while potential improvement of metabolic profile is acknowledged, Meanwell warns of potential context dependent negative consequences.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
For further elaboration, motivation for the routine substitution of CF3 for CH3 comes from Meanwell, who teaches “Replacing hydrogen atoms with fluorine has been explored extensively in drug design, most commonly in the context of a CF3 for CH3 where these substitutions can modulate potency or interfere with metabolic modification” (page 5823, left column, last paragraph; cited in the above rejection). SADBE structurally only has two positions with a CH3 functional group to substitute with CF3; one at the end of each alkyl chain. Meanwell further teaches, “Because the introduction of fluorine can lead to resistance toward oxidative metabolism, fluorination has developed into a popular approach to addressing poor pharmacokinetic performance of compounds in vitro and in vivo” (page 5824, left column, second paragraph, cited in the above rejection).
MPEP 2144.09 states:
A prima facie case of obviousness may be made when chemical compounds have very
close structural similarities and similar utilities. "An obviousness rejection based on
similarity in chemical structure and function entails the motivation of one skilled in the
art to make a claimed compound, in the expectation that compounds similar in
structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245,
254 (CCPA 1979).
As taught by Meanwell, replacement of CH3 with a CF3 is a well-established medicinal chemistry strategy used to modulate potency, improve metabolic stability and enhance pharmacokinetic properties. Given the close structural similarity between compounds, and thus their shared utility, one of ordinary skill in the art would have reasonably expected the modified compound to retain similar biological properties while potentially exhibiting improved performance.
While it is noted Meanwell mentions the fluorination effect in reducing metabolism “can range from negative or null, possibly due to redirecting metabolism to an alternative site, to global protection toward metabolic modification, while the effects exerted on the metabolic stability of proximal functionality can be positive or negative dependent upon context” (page 5824, left column, second paragrpah) the reference does not discourage CF3 for CH3 substitutions; and as noted above, replacement of CH3 with a CF3 is a well-established medicinal chemistry strategy used to modulate potency, improve metabolic stability and enhance pharmacokinetic properties.
"[A] reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed." In re DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009).
Applicant argues:
Applicant contends that Barman discloses many hair-growth promoting agents (pharmaceutical compositions) selected from a group, including SADBE, that can be used in a method for treating alopecia; none of them being the compound of Formula (1).
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Barman teaches a hair growth promoting agent (pharmaceutical composition) selected from a group consisting of the same compounds (SADBE, DPCP, Water, glucocorticoid, minoxidil, finasteride, etc) used for the same exact purpose of treating alopecia related hair loss. As discussed above, SADBE and the compound of Formula (1) are nearly identical, differing only by terminal CF3 for CH3 substitution.
MPEP 2144.09 states:
A prima facie case of obviousness may be made when chemical compounds have very
close structural similarities and similar utilities. "An obviousness rejection based on
similarity in chemical structure and function entails the motivation of one skilled in the
art to make a claimed compound, in the expectation that compounds similar in
structure will have similar properties." In re Payne, 606 F.2d 303, 313, 203 USPQ 245,
254 (CCPA 1979).
The integration of the additional agents or carriers taught by Barman into the topical treatment method of Freyschmidt-Paul, as modified in view of Meanwell, to treat the same alopecia related hair loss would have been merely combining known elements with no change to their respective functions.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Conclusion
Claims 35-39, 41-46, 49-51 and 56-65 are rejected.
No claim is 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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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691