DETAILED ACTION
This office action is in response to the Applicant’s filing dated May 22nd, 2026.
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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 22nd, 2026 has been entered.
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.
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 May 22nd, 2026. Acknowledgement is made of Applicant's amendment of claims 35, 39, 41 and 62.
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 in the context of a CF3 for CH3 replacement, where these substitutions can modulate potency or interfere with metabolic modification” (page 5823, left column, last paragraph).
MPEP § 2144.09(III) states:
“Claimed and prior art compounds used in a method would have been expected to have similar activity because the structural difference between the compounds involved a known bioisosteric replacement” In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
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. One of ordinary skill in the art would have had a reasonable expectation that the closely related compound would retain useful hair growth promoting activity, with the possibility of modulating potency or other pharmacological properties.
“[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.
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).
PNG
media_image1.png
339
470
media_image1.png
Greyscale
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. It is noted there are only two CH3 functional groups present on the compound.
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 in the context of a CF3 for CH3 replacement, where these substitutions can modulate potency or interfere with metabolic modification” (page 5823, left column, last paragraph).
MPEP § 2144.09(III) states:
“Claimed and prior art compounds used in a method would have been expected to have similar activity because the structural difference between the compounds involved a known bioisosteric replacement” In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
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, in light of the teachings of Meanwell that these specific CF3 for CH3 substitutions have been explored extensively in drug design where these substitutions can modulate potency or interfere with metabolic modification. One of ordinary skill in the art would have had a reasonable expectation that the closely related compound would retain useful hair growth promoting activity, with the possibility of modulating potency or other pharmacological properties.
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 replacement of CF3 for CH3 was a known medicinal chemistry strategy in the art, as disclosed by Meanwell, for modifying pharmacodynamic and pharmacokinetic properties while preserving close structural similarity to a lead compound.
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 modulate potency and 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 modulate potency or other pharmacological properties while retaining useful hair growth promoting activity. 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.
Response to Arguments
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.
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 rejections). SADBE structurally only has two positions with a CH3 functional group to substitute with CF3; one at the end of each alkyl chain.
MPEP § 2144.09(III) states:
“Claimed and prior art compounds used in a method would have been expected to have similar activity because the structural difference between the compounds involved a known bioisosteric replacement” In re Dillon, 919 F.2d 688, 16 USPQ2d 1897 (Fed. Cir. 1990).
As taught by Meanwell, replacement of CH3 with a CF3 is a well-established medicinal chemistry strategy capable of modulating potency, metabolic stability and pharmacokinetic properties. Given the close structural similarity between SADBE and the instantly claimed compound, together with SADBE’s established hair growth promoting utility, one of ordinary skill in the art would have had a reasonable expectation that the closely related compound would retain useful hair growth promoting activity, with the possibility of modulating potency or other pharmacological properties.
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.
Obviousness does not require absolute predictability, only a reasonable expectation of success, i.e., a reasonable expectation of obtaining similar properties. See, e.g., In re O’Farrell, 853 F.2d 894, 903, 7 USPQ2d 1673, 1681 (Fed. Cir. 1988)
"[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 the Examiner’s relies on bioisosteric substitution to establish obviousness, citing Mylan Pharmaceuticals Inc. v. Research Corporation Technologies Inc., 2017-2088, 2017-2089, 2017-2091 (Fed. Cir. February 1, 2019).
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
In the above cited case, the Federal Circuit upheld the Board’s finding of no motivation because the case’s record did not explain why bioisosterism would be used to modify that specific compound, and the proposed modification was expected to cause potency loss and significant conformational change. In contrast, in the instant case Meanwell provides motivation for the substitution by express teachings of the particular CF3 for CH3 substitution, further stating this particular substitution is known to modulate potency, and the modification preserves the squaric acid core and alkyl chain structure of SADBE. Thus, unlike the record in Mylan, the instant record supplies both an express reason to make the particular substitution and a close structural basis for expecting retention of useful activity.
Applicant argues:
Applicant contends that modification of SADBE is unpredictable, citing their specification testing other SADBE analogs and their ineffectiveness; specifically, CCl-SADBE and PEG-SADBE.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Applicant’s evidence that certain other SADBE analogs failed to promote hair growth does not negate the legal basis of the rejection. It is not required that every structurally modified analog exhibit identical activity, but that the prior art would have provided one of ordinary skill in the art with motivation to make the proposed modifications leading to the instantly claimed compound with a reasonable expectation of obtaining similar useful properties, see MPEP § 2144.09. In the instant case, Meanwell expressly teaches the particular CF3 for CH3 substitution, further stating this particular substitution is known to modulate potency.
Applicant argues:
Applicant contends that Meanwell’s discussion of metabolic stability provides no motivation in the context of topical treatment.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The rejection does not rely on metabolic stability for the motivation to make the modification. Meanwell expressly teaches CF3 for CH3 substitution where these substitutions can modulate potency or interfere with metabolic modification. Potency remains a therapeutically relevant property regardless of whether the compound is administered topically. Accordingly, even assuming systemic oxidative metabolism is of a reduced concern for topical administration, Meanwell still provides an independent reason to make the expressly taught CF3 for CH3 substitution.
Applicant argues:
Applicant contends that CF3-SADBE demonstrates unexpectedly superior hair growth effects and reduced inflammation relative to SADBE, citing Example 5 and Figure 5.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
The relied upon comparison is primarily qualitative. Figure 5 provides photographic categorical observations at selected time points, but does not provide any quantitative measurements of anagen induction, hair density, hair growth rate or inflammation severity, nor does the specification provide statistical analysis or other objective quantitative evidence establishing the significance of the apparent differences between the two groups.
Moreover, the photographs themselves are of low resolution and clarity, the Examiner is unable to verify the asserted categorical distinction that CF3-SADBE exhibited visible anagen at day 10, whereas SADBE did not. The SADBE image at day 10 does not permit the Examiner to independently verify the Applicant’s categorical assertion that visible anagen is absent, particularly given the image’s low-resolution and lack of an objective scoring criteria.
Similarly, although the specification states that SADBE produced more visible inflammation at day 14, no quantitative inflammation score or other objective analysis is provided to establish the magnitude or significance of that difference.
Thus, while the evidence has been considered, the Applicant has not persuasively established that the observed differences represent unexpectedly superior effects of sufficient, practical and evidentiary significance to outweigh the strong prima facie obviousness case arising form the very close structural relationship, common utility and Meanwell’s express teaching of the particular CF3 for CH3 substitution.
Conclusion
Claims 35-39, 41-46, 49-51 and 56-65 are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHRISTOPHER L JOHNSON whose telephone number is (571)272-1672. The examiner can normally be reached Monday - Friday 08:00AM - 5:00PM EST with Flex on Fridays.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached at (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
Prosecution Insights