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 .
Priority
Acknowledgement is made of Applicant’s submission of translated foreign priority documents for KR10-2021-0141684 and KR10-2022-0079197 on 07/31/2026; however, these English translated documents are not certified. Therefore, the effective filing date of the instant application is 07/06/2022.
Should applicant desire to obtain the benefit of foreign priority under 35 U.S.C. 119(a)-(d) prior to declaration of an interference, a certified English translation of the foreign application must be submitted in reply to this action. 37 CFR 41.154(b) and 41.202(e).
Failure to provide a certified translation may result in no benefit being accorded for the non-English application.
Maintained Rejections
Claim Rejections - 35 USC § 103, Obviousness
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 1-11 and 18 are rejected under 35 U.S.C. 103 as being unpatentable over Lee (US 2017/0246266; Date of Publication: August 31, 2017) in view of Schwartz (U.S. Patent No. 6,299,893; Date of Publication: October 9, 2001).
Lee’s general disclosure relates to “a novel cell penetrating peptide; a cell penetrating botulinum toxin recombinant protein composition in which the cell penetrating peptide and the light chain of a botulinum toxin are fused; and a use thereof and, more specifically, to a composition enabling the transdermal delivery of a cell penetrating botulinum toxin recombinant protein and capable of being locally used for various treatments of the skin and cosmetic purposes. The cell penetrating peptide-botulinum toxin recombinant protein of the present invention can be transdermally delivered, thereby having the intrinsic effect of a botulinum toxin and simultaneously having greater convenience of use, and thus can be effectively applied as a local agonist for the treatment of various diseases and aesthetic and/or cosmetic purposes” (see, e.g., Lee, abstract).
Regarding claim 1 pertaining to a composition comprising a botulinum toxin recombinant protein, Lee teaches a botulinum toxin recombinant protein (see, e.g., Lee, abstract), wherein a “cell penetrating peptide and the light chain of a botulinum toxin are fused” (see, e.g., Lee, abstract). Moreover, Lee teaches SEQ ID NO: 1, which is the cell penetrating peptide, and which has 100% sequence identity to instant SEQ ID NO: 1 (see, e.g., Lee, [0016] & Office Action Appendix). Lee teaches “The present invention provides a cell-penetrating botulinum toxin recombinant protein in which the cell-penetrating peptide consisting of the amino acid sequence of SEQ. ID. NO: 1 is conjugated with one or both termini of the light chain of botulinum toxin” (see, e.g., Lee, [0019]). Regarding the therapeutically effective amount, Lee teaches 2.5 µM, 5 µM, and 10 µM of the botulinum recombinant protein exhibits “excellent cell penetration potential in keratinocytes” (see, e.g., Lee, Example 2, [0122]). Furthermore, Lee teaches “an amount of a light chain or light chain derivative of skin-penetrating and a nerve terminus cell-penetrating botulinum toxin, which is sought in the present invention, should be limited to a concentration of 1 to 10 ppm in order to ensure safety” (see, e.g., Lee, [0011]); therefore, one of ordinary skill in the art would be motivated to test and use the botulinum toxin recombinant protein at a concentration between 1 to 10 ppm, or below 1 ppm, in order to ensure safety, while also testing for hair growth.
Regarding claim 2 pertaining to the botulinum toxin recombinant protein, Lee teaches SEQ ID NO: 45, which encodes for the botulinum toxin recombinant protein, and which has 100% sequence identity to instant SEQ ID NO: 45 (see, e.g., Lee, [0020] & Office Action Appendix).
Regarding claim 3 pertaining to the botulinum toxin light chain, Lee teaches SEQ ID NO: 38, which has 100% sequence identity to instant SEQ ID NO: 3 (see, e.g., Lee, [0020] & Office Action Appendix).
Regarding claim 4 pertaining to the botulinum toxin light chain having a hexahistidine tag, Lee teaches “the light chain of botulinum toxin may further comprise a hexahistidine tag at one terminus” (see, e.g., Lee, [0022]).
Regarding claim 5 pertaining to the botulinum toxin light chain serotype, Lee teaches “the light chain of botulinum toxin may be selected from the group consisting of botulinum toxin serotypes A, B, C, D, E, F and G” (see, e.g., Lee, [0023]).
Regarding claim 6 pertaining to fusion of the cell-penetrating peptide, Lee teaches “the conjugation may be conjugation of the cell-penetrating peptide to a carboxyl terminus or an amino terminus of the light chain of botulinum toxin, or both termini thereof” (see, e.g., Lee, [0024]).
Regarding claim 7 pertaining to the bond for the fusion, Lee teaches “the conjugation may be achieved by a peptide bond or a covalent bond” (see, e.g., Lee, [0025]).
Regarding claims 8-10 pertaining to the composition promoting different effects, Lee teaches the same composition (see, e.g., Lee, abstract), [0016], [0019], [0020], and [0022]-[0024]), as well as administration of the same composition (see, e.g., Lee, [0032]), therefore, the composition would inherently be capable of proliferation of dermal papilla cells, promotion of prostaglandin F2α expression, promotion of hair growth, and reduction in androgenetic alopecia or telogen effluvium (see, e.g., MPEP 2112.01(I)-(II)).
Regarding claim 11 pertaining to transdermal administration, Lee teaches “the pharmaceutical composition may be used for transdermal administration” (see, e.g., Lee, [0032]).
Regarding claim 18 pertaining to the composition, Lee teaches that the composition may be a cosmetic composition used for dermatological treatments and cosmetological purposes (see, e.g., Lee, [0014]). Lee also teaches that the composition is a pharmaceutical composition that can be used to treat facial spasms, eyelid spasms, torticollis, blepharospasm, cervical dystonia, oropharynx dystonia, spasmodic dysphonia, migraines, and hyperhidrosis (see, e.g., Lee, [0031]).
However, Lee does not teach: a therapeutically effective amount for the treatment of androgenetic alopecia or telogen effluvium (claim 1); or administration to a subject in need thereof (i.e., a subject with androgenetic alopecia or telogen effluvium) (claim 1).
Schwartz’s general disclosure relates to “a method for reduction of hair loss and stimulation of hair growth on the scalp of a human patient. The method comprises the step of administering a presynaptic neurotoxin into the scalp of the patient in a quantity and concentration to provide a therapeutically-effective flaccid paralysis of the muscle tissue outside of the skull of the patient. The result is a reduction in tissue tension in the desired area of hair-growth without affecting any tissue not outside the skull of the patient” (see, e.g., Schwartz, abstract).
Regarding claim 1 pertaining to administration of a therapeutically effective amount to a subject with androgenetic alopecia, Schwartz teaches “a method of treating the scalp to reduce hair loss and stimulate hair growth on the scalp” (see, e.g., Schwartz, col 1, lines 5-7), wherein the method comprises administration of a presynaptic neurotoxin, such as botulinum toxin A (see, e.g., Schwartz, col 1, lines 65-66 & col 2, lines 40-41), to a subject in need of hair growth (see, e.g., Schwartz, col 1, lines 63-64 & col 4, lines 41-45), such as a subject with male pattern baldness, otherwise known as androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59). Moreover, Schwartz teaches administration of 0.1 ml of botulinum toxin diluted to 10 units per 0.1 ml to a patient’s scalp (see, e.g., Schwartz, col 3, lines 44-46). More specifically, Schwartz teaches a case study wherein “A healthy 39 year old non-smoker with Hamilton class V male pattern baldness was injected intramuscularly with 100 units BTX-A diluted to 10 units per 0.1 ml in normal saline. The frontal, temporal, peri-auricular and occipital muscles were injected with a fine gauge hypodermic needle in a circumferential manner around the periphery of the scalp as described above. The vertex was photographed as well, position of frontal sentinel hairs and average daily hair loss collected in a fine toothed comb. At 6 months scalp tension increased and a further 100 unite of botulinum toxin A was injected in a manner similar to the first injection. At 1 year, post treatment, daily hair loss was reduced by 76 percent and the frontal sentinel hair was 1 cm forward of its predecessor” (see, e.g., Schwartz, col 4, lines 41-55).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to produce Lee’s botulinum toxin recombinant protein, wherein the protein is administered to treat hair loss in patients, as taught by Schwartz. One would have been motivated to do so because Schwartz teaches “The inventors have found that injection of a presynaptic neurotoxin improves the tissue environment surrounding the hair follicles by reducing scalp tension and, by doing so, improves bloodflow through the arteries. In turn, the tension in hair-bearing tissue is reduce and hair growth is stimulated” (see, e.g., Schwartz, col 4, lines 35-40). Moreover, Lee teaches that the botulinum toxin composition comprises a cell penetrating peptide that is “capable of mediating intracellular delivery of a biologically active molecule, wherein the cell-penetrating peptide is designed to effectively transmit a botulinum toxin protein which is difficult to be delivered through the skin because of a molecular weight and the intrinsic characteristics of a skin cornified layer” (see, e.g., Lee, [0012]). Additionally, Lee teaches “the cell-penetrating peptide itself may not have a defined enzymatic or biological therapeutic activity, but serves as a carrier facilitating intracellular transduction through the cell membrane” (see, e.g., Lee, [0085]). Therefore, based on the teachings of Lee and Schwartz, it would be obvious to produce the Lee’s botulinum toxin recombinant protein for treatment of hair loss, as taught by Schwartz, because then the recombinant protein can be effectively delivered into the skin of the scalp of a patient in order to stimulate hair growth. One would have expected success Lee and Schwartz both teach administration of botulinum toxin for cosmetic purposes.
Examiner’s Response to Arguments
Applicant's arguments filed 07/31/2026 have been fully considered but they are not persuasive.
Regarding Applicant’s argument that neither Lee nor Schwartz teach treating androgenetic alopecia or telogen effluvium (remarks, page 8), this argument is not persuasive because Schwartz teaches administration of a presynaptic neurotoxin, such as botulinum toxin A (see, e.g., Schwartz, col 1, lines 65-66 & col 2, lines 40-41), to a subject in need of hair growth (see, e.g., Schwartz, col 1, lines 63-64 & col 4, lines 41-45), such as a subject with male pattern baldness, otherwise known as androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59). Therefore, Schwartz does indeed teach a subject with androgenetic alopecia (i.e., male pattern baldness).
Regarding Applicant’s argument that Lee contains no disclosure of administering the recombinant protein to treat a subject with androgenetic alopecia or telogen effluvium (remarks, page 9), this argument is not persuasive because Lee was not relied upon to teach these claim limitations. Instead, as discussed above, Schwartz was relied upon to teach treatment of patients with androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59). Applicant is arguing against the references individually and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
Regarding Applicant’s argument that there is no reasonable expectation of success for administration of Lee’s recombinant protein for treatment of androgenetic alopecia (remarks, page 9), this argument is not persuasive. Schwartz teaches “The inventors have found that injection of a presynaptic neurotoxin improves the tissue environment surrounding the hair follicles by reducing scalp tension and, by doing so, improves bloodflow through the arteries. In turn, the tension in hair-bearing tissue is reduce and hair growth is stimulated” (see, e.g., Schwartz, col 4, lines 35-40). Lee teaches that a botulinum toxin light chain is fused with a cell penetrating peptide for transdermal delivery and “thus can be effectively applied as a local agonist for the treatment of various diseases and aesthetic and/or cosmetic purposes” (see, e.g., Lee, abstract). Moreover, Lee teaches that the cell penetrating peptide is “capable of mediating intracellular delivery of a biologically active molecule, wherein the cell-penetrating peptide is designed to effectively transmit a botulinum toxin protein which is difficult to be delivered through the skin because of a molecular weight and the intrinsic characteristics of a skin cornified layer” (see, e.g., Lee, [0012]). Additionally, Lee teaches “the cell-penetrating peptide itself may not have a defined enzymatic or biological therapeutic activity, but serves as a carrier facilitating intracellular transduction through the cell membrane” for delivery of the botulinum light chain (see, e.g., Lee, [0085]). Since Lee teaches that the recombinant botulinum toxin protein can be administered for aesthetic and/or cosmetic purposes (see, e.g., Lee, abstract), one of ordinary skill in the art would have motivation to apply this to the teachings of Schwartz, as Schwartz teaches administration of botulinum toxin for the treatment of androgenetic alopecia, which is an aesthetic and/or cosmetic purpose.
Regarding Applicant’s arguments pertaining to Examples 1-3 (remarks, pages 9-10), these results are not commensurate in scope with the claimed invention. Example 1 relies on HFDPCs inoculated at 1x106 cells/dish, and cultured with penicillin and streptomycin at 37oC containing 5% carbon dioxide (see, e.g., instant specification, pg. 29, lines 16-21). Furthermore, Example 1 tested cell viability with thiazolyl blue tetrazolium bromide by adding the recombinant botulinum protein at various concentrations (see, e.g., instant specification, pg. 30, lines 1-8). Example 2 relies on preparation of the recombinant botulinum protein at a concentration 2000-fold that of the finished product, along with 0.1% niacinamide, 0.2% dexapanthenol diluted in cell culture medium (see, e.g., instant specification, pg. 33, lines 5-11). Additionally, Example 2 relies on treatment of keratinocytes that were inoculated at 3x105 cells per 6 wells for two days and one day in a starvation state (see, e.g., instant specification, pg. 33, lines 14-16). Example 3 relies on 4 men (42 to 52 years old) with alopecia symptoms applying 2.5 cc of the botulinum toxin recombinant protein every morning (see, e.g., instant specification, pg. 37, lines 7-11). Overall, these treatment conditions in Examples 1-3 are not part of the instantly claimed invention; therefore, the results argued by Applicant are not commensurate in scope with the claimed invention.
Regarding Applicant’s argument that Lee is distinguishable from the claimed invention as it pertains to specific medial use, target subjects, and therapeutic effects (remarks, page 10), this argument is not persuasive because Applicant is arguing against the references individually and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). The combination of Lee and Schwartz teaches the instantly claimed invention wherein Lee teaches the claimed botulinum toxin recombinant protein for administration for aesthetic and/or cosmetic purposes” (see, e.g., Lee, abstract), and Schwartz teaches administration of botulinum toxin for treatment of androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59). Therefore, both teach administration of botulinum toxin for cosmetic purposes. Moreover, one would have been motivated to combine Lee’s botulinum toxin recombinant protein for treatment of androgenetic alopecia, as taught by Schwartz, because Lee teaches that the botulinum toxin recombinant protein contains a cell-penetrating peptide that mediates intracellular delivery of the biologically active botulinum protein, “which is difficult to be delivered through the skin because of a molecular weight and the intrinsic characteristics of a skin cornified layer” (see, e.g., Lee, [0012]), and Schwartz teaches that botulinum toxin can be administered to treat androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59).
Regarding Applicant’s argument that Schwartz discloses a botulinum toxin inject therapy that differs from the present invention, route of administration, and mechanism of action (remarks, page 11), this argument is not persuasive because, as discussed above, Applicant is arguing against the references individually and one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. Schwartz was not relied upon to teach the route of administration or injection therapy because Lee was relied upon in the above presented rejection to teach these limitations. Lee teaches a botulinum toxin recombinant protein (see, e.g., Lee, abstract), wherein a “cell penetrating peptide and the light chain of a botulinum toxin are fused” (see, e.g., Lee, abstract). Moreover, Lee teaches SEQ ID NO: 1, which is the cell penetrating peptide, and which has 100% sequence identity to instant SEQ ID NO: 1 (see, e.g., Lee, [0016] & Office Action Appendix). Lee teaches “The present invention provides a cell-penetrating botulinum toxin recombinant protein in which the cell-penetrating peptide consisting of the amino acid sequence of SEQ. ID. NO: 1 is conjugated with one or both termini of the light chain of botulinum toxin” (see, e.g., Lee, [0019]). Moreover, Lee teaches “the pharmaceutical composition may be used for transdermal administration” (see, e.g., Lee, [0032]). Therefore, Lee teaches the instantly claimed botulinum toxin recombinant protein and the same injection route. Additionally, Lee teaches that the botulinum toxin recombinant protein can be administered for treatment of aesthetic and/or cosmetic purposes” (see, e.g., Lee, abstract). As previously stated, Schwartz was relied upon to teach that botulinum toxin can be administered for treatment of androgenetic alopecia (see, e.g., Schwartz, col 1, lines 28-31 & 56-59). One would have been motivated to apply administration of the botulinum toxin recombinant protein, as taught by Lee, to the treatment of androgenetic alopecia, as taught by Schwartz, because Lee teaches that the botulinum toxin recombinant protein contains a cell-penetrating peptide that mediates intracellular delivery of the biologically active botulinum protein, “which is difficult to be delivered through the skin because of a molecular weight and the intrinsic characteristics of a skin cornified layer” (see, e.g., Lee, [0012]). Moreover, as it pertains to promotion of dermal papilla cell proliferation and increased PGF2α expression, Applicant argues that the composition is characterized in that the recombinant protein is transdermally delivered to act on dermal papilla cell and keratinocytes; however, this is not part of the instantly claimed invention. Applicant claims that the instantly claimed composition promotes proliferation of dermal papilla cells and promotes PGF2α expression (instant claims 7-8); however, the instantly claimed composition is taught by Lee; therefore, the composition would be capable of performing the intended use of proliferation of dermal papilla cells and promotion of PGF2α expression. Moreover, in terms of the method, the combined prior art of Lee and Schwartz teaches the instantly claimed method which would inherently result in proliferation of dermal papilla cells and promotion of PGF2α expression.
Regarding Applicant’s argument that the combination of Lee and Schwartz do not render the claimed method obvious because one of ordinary skill it the art would not reasonably expect that replacing the full-length botulinum toxin of Schwartz with the light chain taught by Lee would result in the same therapeutic effect of treating alopecia (remarks, page 13), this argument is not persuasive. Lee teaches that the botulinum toxin heavy chain is used for cell entry, while the light chain is released in the cell to provide actual pharmacological, aesthetic, and/or cosmetic effects (see, e.g., Lee, [0003], [0041], [0069]-[0071]). Therefore, since the light chain is the part of the toxin actually providing the effects, Lee fused the light chain to a novel cell penetrating peptide in order to more efficiently deliver the toxin to the skin and to a neuronal cell (see, e.g., Lee, [0072]). Moreover, Lee teaches that the cell penetrating peptide is “capable of mediating intracellular delivery of a biologically active molecule, wherein the cell-penetrating peptide is designed to effectively transmit a botulinum toxin protein which is difficult to be delivered through the skin because of a molecular weight and the intrinsic characteristics of a skin cornified layer” (see, e.g., Lee, [0012]). Therefore, the cell penetrating peptide that is fused to the light chain allows for efficient delivery of the light chain to the skin since the botulinum toxin by itself is difficult to deliver through the skin, and this would be important and advantageous when delivering botulinum toxin for treatment of androgenetic alopecia, as taught by Schwartz, since one would have to deliver the botulinum toxin through the skin.
Regarding Applicant’s argument that that the teachings of Lee were selectively combined (remarks, page 13), this argument is not persuasive because Lee teaches “In the present invention, the term “cell-penetrating botulinum toxin recombinant protein” refers to a conjugate comprising a novel cell-penetrating peptide TD1 and the light chain of botulinum toxin, which are chemically linked by a peptide bond or covalent bond. That is, the cell-penetrating botulinum toxin recombinant protein delivers the light chain of botulinum toxin into a cell with high efficiency by conjugating a specific cell-penetrating peptide with the light chain of botulinum toxin, which is a macromolecule that is difficult to be introduced into the cell, to give a cell penetrating potential. Here, the conjugation may be made between the cell-penetrating peptide and a carboxyl terminus, an amino terminus or both termini of the light chain of botulinum toxin” (see, e.g., instant specification, [0090]). These limitations were not “scattered’ throughout Lee as Applicant argues, but instead disclosed in the same paragraph.
Regarding Applicant’s argument that there are no inherent effects resulting from Lee (remarks, page 14), this argument is not persuasive because, as discussed above, Applicant claims that the instantly claimed composition promotes proliferation of dermal papilla cells and promotes PGF2α expression (instant claims 7-8); however, the instantly claimed composition is taught by Lee; therefore, the composition would be capable of performing the intended use of proliferation of dermal papilla cells and promotion of PGF2α expression. Moreover, in terms of the method, the combined prior art of Lee and Schwartz teaches the instantly claimed method which would inherently result in proliferation of dermal papilla cells and promotion of PGF2α expression. Applicant argues that there is no sufficient experimental or technical support; however, the Patent and Trademark Office is not equipped to conduct experimentation to determine if and how Applicant’s compositions, methods, and experimental results differ from the prior art. The combined prior art of Lee and Schwartz teaches administration of the exact same botulinum toxin recombinant protein to the exact same patient population, which inherently would result in treatment of androgenetic alopecia, proliferation of dermal papilla cells and promotion of PGF2α expression. Furthermore, in instant claims 7-8, Applicant claims that the composition is capable of promoting proliferation of dermal papilla cells and promotion of PGF2α expression, and Lee teaches the same composition as the instantly claimed invention; therefore, the composition would inherently be capable of promoting proliferation of dermal papilla cells and promotion of PGF2α expression. The cited art is taken as a whole demonstrates administration of the same botulinum toxin recombinant fusion protein, that is administered to the same patient population. Therefore, the burden of establishing novelty or nonobviousness by objective evidence is shifted to the Applicant.
Conclusion
Claims 1-11 and 18 are rejected.
No claims are 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.
Correspondence Information
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NATALIE IANNUZO whose telephone number is (703)756-5559. The examiner can normally be reached Mon - Fri: 8:30-6:00 EST.
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/NATALIE IANNUZO/Examiner, Art Unit 1653
/SHARMILA G LANDAU/Supervisory Patent Examiner, Art Unit 1653
