DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of the Claims
Claims 1-2, 4-18, and 27-29 are pending (claim set as filed on 10/31/2025).
Priority
This application filed on 07/22/2020 has a provisional application no. 62/877,155 filed on 07/22/2019.
Withdrawal of Rejections
The response and amendments filed on 10/31/2025 are acknowledged. Any previously applied minor objections and/or minor rejections (i.e., formal matters), not explicitly restated herein for brevity, have been withdrawn necessitated by Applicant’s formality corrections and/or amendments. For the purposes of clarity of the record, the reasons for the Examiner’s withdrawal, and/or maintaining if applicable, of the substantive or essential claim rejections are detailed directly below and/or in the Examiner’s response to arguments section.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
Claim Interpretation
The MPEP 2103(I)(C) states that:
“For processes, the claim limitations will define steps or acts to be performed”;
“For products, the claim limitations will define discrete physical structures or materials. Product claims are claims that are directed to either machines, manufactures or compositions of matter”.
However, note that Applicant’s claimed invention is drawn to a product (more specifically, a composition of matter) because base claim 1’s preamble explicitly recites “A topical composition” (MPEP 2111.02: Effect of the Preamble). In other words, the claimed invention, as a whole, falls under the statutory category of invention as a product claim not a process.
Regarding base claim 1’s preamble of “for treating hair loss in a subject”, this phrase is not given patentable weight because it describes the intended use of the composition. The MPEP at 2111.02(II): Effect of the Preamble states “If the body of a claim fully and intrinsically sets forth all of the limitations of the claimed invention, and the preamble merely states, for example, the purpose or intended use of the invention, rather than any distinct definition of any of the claimed invention’s limitations, then the preamble is not considered a limitation and is of no significance to claim construction”.
Regarding base claim 1’s phrase of “via a process that includes passive diffusion into exosomes membranes in the presence of HPbCD” and dependent claim 18’s phrase of “was generated under hyperbaric O2 conditions” are interpreted as a product-by-process limitations. The MPEP at 2113(I) states that “even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process”.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC §112(d), Failing to Further Limit
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS - Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 5, 8, and 13 are rejected under 35 U.S.C. 112(d) as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Base claim 1 was amended to recite “an exosome derived from bovine raw milk”. However, dependent claims 5, 8, and 13 also require the limitation of “a bovine raw milk exosome” and therefore, it is considered to be duplicate limitations which does not further limit base claim 1.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
New Grounds of Rejection Necessitated by Amendment
Claim Rejections - 35 USC §112(a), New Matter
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
Claims 1-2, 4-18, and 27-29 are rejected under 35 U.S.C. 112(a) as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor at the time the application was filed, had possession of the claimed invention.
Base claim 1 was amended to recite the phrase “resulting in improved minoxidil bioavailability and enhanced follicular penetration compared to free minoxidil”. However, after a review of ¶ [0065]-[0069] & [0086] that Applicant pointed to for support and in addition to a text search of the specification, there is no mention of “bioavailability”, “enhanced follicular penetration”, nor “compared to free minoxidil” and therefore, the amended limitation is considered to be new matter. Applicant is invited to direct the Examiner’s attention to the instant specification to illustrate, for example, the claimed composition’s improved characteristics of bioavailability and enhanced follicular penetration with side-by-side comparative objective data against free minoxidil.
Claims 2, 4-18, and 27-29 are rejected because they are dependent claims that do not overcome the deficiencies of the rejected claim from which they depend.
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.
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Claims 1-2, 4-9, 11-14, 16-17, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Lim (US 2017/0135915 A1) in view of Gupta (US 2016/0000710 A1 - cited in the IDS filed on 05/03/2023) and Tamarkin (US 2008/0260655 A1).
Lim’s general disclosure relates to the field of cosmetics and medicine; and in particular, treatments of alopecia or hair loss (see ¶ [0002]-[0008]). Lim discloses that there are only two approved marketed drugs for the treatment of male pattern baldness which are 5% minoxidil and finasteride (see ¶ [0009]-[0014]).
Lim teaches “an exosome for the preparation of a pharmaceutical composition to promote or enhance would healing or hair growth, or both, in an individual. The exosome may be derived from a stem cell such as a mesenchymal stem cell (MSC)” (see abstract & ¶ [0016]-[0020]). Lim teaches the pharmaceutical composition may be applied topically (see ¶ [0029], [0045]).
Regarding claims 7 and 11-12 pertaining to the additional ingredients, Lim teaches the exosome compositions includes a carrier such as moisturizing agents, solubilizing agents, penetration enhancers, et al. (see ¶ [0190]-[0191]). Moisturizing agents is a substance that adds or restores moisture to the skin include allantoin or hyaluronic acid (see ¶ [0192]). Emulsifiers are used to promote the formation and stabilization of an emulsion such as methyl cellulose or polyethylene glycol (see ¶ [0198]). Solubilizing agents are used to enable solutes to dissolve such as cyclodextrins (see ¶ [0200]). Anti-irritant agents are used to prevent or reduces soreness, roughness, or inflammation such as allantoin (see ¶ [0192]).
However, Lim does not teach: loaded with minoxidil and hydroxypropyl-β-cyclodextrin (claim 1’s limitation); or a bovine raw milk exosome (claims 2, 5, 8, 13, 16, and 28).
Gupta’s general disclosure relates to milk-derived microvesicle compositions and methods of isolating and using the same for the treatment of disease (see ¶ [0003]). Gupta discloses the term microvesicle is used interchangeably with the terms nanoparticle, liposome, exosome, exosome-like particle, and nano-vector (see ¶ [0070]). Gupta teaches “a composition is provided that comprises a therapeutic agent encapsulated by a milk-derived microvesicle. The compositions can include therapeutic agents such as phytochemical agents or chemotherapeutic agents, while the milk-derived microvesicle can be derived from raw milk or colostrum” (see abstract & ¶ [0008], [0068]). The compositions can further be formulated as topical semi-solid ointment or cream formulation (see ¶ [0088], [0093]).
Gupta teaches the effect of therapeutic agent-loaded milk-derived exosomes wherein activity was observed when exosomal concentration was kept constant and the therapeutic agent concentration varied, implying some intrinsic protective effects of the exosomes (see ¶ [0124], [0005]). Gupta further teaches that milk and colostrum exosomes can be loaded with a variety of hydrophilic and lipophilic compounds wherein therapeutic agents embedded in exosomes showed higher anti-inflammatory activities than free therapeutic agents (see ¶ [0132], [0134]).
Regarding claims 2, 5, 8, 13, 16, and 28 pertaining to a bovine milk exosome, Gupta discloses milk-derived microvesicle from milk of female mammals; wherein exosomes can be isolated from bovine milk and colostrum (see ¶ [0072]-[0074], [0134]). The milk-derived microvesicle can be derived from raw milk or colostrum (see ¶ [0008], [0068]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load exosomes with a therapeutic agent such as taught by Gupta in the composition of Lim. The ordinary artisan would have been motivated to do so because Gupta suggests that milk exosomes can be loaded with a variety of therapeutic compounds and imply that said exosomes may have protective effects and anti-inflammatory activity than free therapeutic agents (see teaching-suggestion-motivation (TSM) by Gupta at ¶ [0124], [0132], [0134]). Thus, an ordinary artisan would have envisage “an exosome loaded with minoxidil” because Lim discloses that minoxidil is a well-known approved first line therapy for the treatment of hair loss (see Lim at ¶ [0008]-[0011]). The ordinary artisan would have had a reasonable expectation of success is because both references are directed to the use of exosomes and Gupta provides a methodology for exosome encapsulation or loading.
Furthermore, in regards to the claimed limitations of additional ingredients (e.g. hydroxypropyl-β-cyclodextrin (HPbCD), vitamins, methyl cellulose, other polymers), it would have secondly obvious to employ or use the additional adjuvants/excipients in the composition of Lim-Gupta. For example, the primary reference of Lim teaches “the term “solubilizing agents” refers to those substances that enable solutes to dissolve. Representative examples of solubilizing agents that are usable include, without limitation, complex-forming solubilizers such as … cyclodextrin” (see Lim at ¶ [0200]). Furthermore, in the pharmaceutical arts, the claimed excipients are well-known, common adjuvant/excipient, or routinely employed in cosmetic or pharmaceutical formulations. The disclosure of Tamarkin is general teaching of pharmaceutical compositions and manufacturing processes thereof to illustrate well-known ingredients and common practices within the purview of the ordinary artisan. For example, the disclosure of Tamarkin discloses polymeric agent serves to stabilize the foam composition and to control drug residence in the target organ (see Tamarkin at ¶ [0394]). Tamarkin further discloses “mucoadhesive polymers includes natural and chemically modified cyclodextrin, especially hydroxypropyl-β-cyclodextrin. Such polymers may be present as free acids, bases, or salts, usually in a final concentration of about 0.01 % to about 0.5% by weight. Many mucoadhesive agents are known in the art to also possess gelling properties” (see ¶ [0397]-[0401]). In other words, HPbCD is a routinely employed to function as a stabilizing or solubilizing adjuvant agent to produced the desired viscosity dependent upon the desired topical formulation (e.g. gel, foam, cream, aerosol, etc.). Furthermore, Tamarkin teaches examples of active agents include vitamin A, vitamin B, vitamin E (see Tamarkin at ¶ [0422]) and “skin bleaching and lightening agents (e.g., hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioning agents (e.g., humectants, moisturizers, etc.), skin soothing and/or healing agents (e.g., panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol, and dipotassium glycyrrhizinate), skin treating agents, and vitamins and derivatives thereof” (see Tamarkin at ¶ [0456]-[0457]). Therefore, in the absence of unexpected results or demonstrating the criticality of the claimed additives/excipients/adjuvants, these limitations are considered to be well-known and routinely employed in the pharmaceutical arts such as disclosed by the Tamarkin reference.
Claims 6, 9-10, 14-15, 17-18, and 29 are rejected under 35 U.S.C. 103 as being unpatentable over Lim in view of Gupta and Tamarkin as applied to claims 1-2, 4-9, 11-14, 16-17, and 27-28 above, and in further view of Cooper (US 2019/0192576 A1) or Kellner (WO 2017/001649) - both references cited in the IDS filed on 05/03/2023.
The modified teachings of Lim in view of Gupta and Tamarkin is discussed above as it pertains to a topical composition for treating hair loss in a subject, the composition comprising an exosome loaded with minoxidil and hydroxypropyl-β-cyclodextrin.
However, the cited references do not specifically teach: an A-MSC exosome (claims 10 and 17-18); or an MSC secretome (claims 6, 9, 14, and 29); or an umbilical cord MSC exosome/secretome (claim 15).
Cooper teaches pharmaceutical formulations that can include an amount of adipose stem cell derived exosomes (see abstract & ¶ [0005]). The pharmaceutical formulation can be administered topically (see ¶ [0007]). Cooper discloses “conditioned media contains the ADSC secreted factors. The secretome of ADSC from CM contains a number of highly conserved proteins that have roles in angiogenesis, regeneration, and extracellular matrix remodeling. It was observed that exosomes isolated from CM contained in large concentrations of MALATl IncRNA” (see ¶ [0132]).
Kellner teaches a method of deriving secretomes from mesenchymal stem cells (see abstract & page 1, lines 4-6). Kellner teaches commonly used tissues for the isolation of MSC are bone marrow, umbilical cord, cord lining and - increasingly - adipose tissue, which has a superior amount of MSCs (see page 1, lines 13-15).
It would have been obvious to employ or use the A-MSC or umbilical cord MSC exosome/secretome such as taught by Cooper or Kellner in the modified teachings of Lim-Gupta-Tamarkin. The ordinary artisan would have been motivated to do so is because Cooper suggests secretome of ADSC from CM contains a number of highly conserved proteins that have roles in angiogenesis, regeneration, and extracellular matrix remodeling; or that Kellner discloses that umbilical cord or adipose derived MSC secretome are common sources for isolation. Thus, the MPEP 2141(III) provides examples of rationales that may support a conclusion of obviousness include: (a) combining prior art elements according to known methods to yield predictable results; (b) simple substitution of one known element for another to obtain predictable results.
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Claims 1-2, 4-9, 11-14, 16-17, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Levi (US 2013/0209528 A1) in view of Gupta (US 2016/0000710 A1 - cited in the IDS filed on 05/03/2023) and Tamarkin (US 2008/0260655 A1).
Levi’s general disclosure relates to the fields of medicine, cell biology, molecular biology and genetics; and also relates to the field of cosmetics and medicine (see ¶ [0001]).
Levi teaches “the use of an exosome for the preparation of a pharmaceutical composition to promote or enhance would healing or hair growth, or both, in an individual. The exosome may be derived from a stem cell such as a mesenchymal stem cell (MSC)” (see abstract & ¶ [0042], [0047], [0079]). Levi teaches the pharmaceutical composition may be topically applied (see ¶ [0028]).
Regarding claims 7, 11-12, and 29, Levi teaches the exosome compositions includes a carrier such as moisturizing agents, solubilizing agents, penetration enhancers, et al. (see ¶ [0188]-[0189]). Moisturizing agents is a substance that adds or restores moisture to the skin include allantoin or hyaluronic acid (see ¶ [0190]). Emulsifiers are used to promote the formation and stabilization of an emulsion such as methyl cellulose or polyethylene glycol (see ¶ [0196]). Solubilizing agents are used to enable solutes to dissolve such as cyclodextrins (see ¶ [0198]). Anti-irritant agents are used to prevent or reduces soreness, roughness, or inflammation such as allantoin (see ¶ [0201]).
However, Levi does not teach: loaded with minoxidil and hydroxypropyl-β-cyclodextrin (claim 1’s limitation); or a bovine raw milk exosome (claims 2, 5, 8, 13, 16, and 28).
Gupta’s and Tamarkin’s teachings are discussed above and reprised herein (omitted herein for the sake of brevity).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load exosomes with a therapeutic agent such as taught by Gupta in the composition of Levi. The ordinary artisan would have been motivated to do so is because of the reasons discussed above by the Gupta reference.
Furthermore, in regards to the claimed limitations of additional ingredients (e.g. hydroxypropyl-β-cyclodextrin (HPbCD), vitamins, methyl cellulose, other polymers), it would have secondly obvious to employ or use the additional adjuvants/excipients in the composition of Levi-Gupta for the reasons discussed above by the Tamarkin reference.
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Claims 1-2, 4-9, 11-14, 16-18, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Al-Qahtani (US 2015/0023908 A1 - cited in the IDS filed on 05/03/2023) in view of Gupta (US 2016/0000710 A1 - cited in the IDS filed on 05/03/2023) and Tamarkin (US 2008/0260655 A1).
Al-Qahtani’s general disclosure relates to skin care compositions, including cosmeceuticals, for topical application, and more particularly, a skin cream, comprising exosomes and cell culture medium conditioned by cells grown in two-dimensional culture (see abstract & ¶ [0002]).
Al-Qahtani teaches treatment of a condition of the skin or hair of a subject which includes decreasing hair loss or enhancing the retention of scalp hair (in male and female pattern baldness) (see ¶ [0021]-[0022], [0088]). Al-Qahtani teaches topical compositions comprising exosomes which may be obtained or derived from mesenchymal stem cells (see ¶ [0051], [0057]). In addition to the growth factors found in the conditioned media, other active agents, such as minoxidil can be used (see ¶ [0138]-[0139]).
Regarding claim 4, Al-Qahtani teaches other ingredients often used in media formulations include fat soluble vitamins including vitamin A (see ¶ [0067], [0069]).
Regarding claim 18, Al-Qahtani teaches exosome production may be induced/enhanced in such cells by cytokine/mitogen exposure, uptake of latex beads, Ca+2 exposure, hypoxia, or other manipulations of the cell culture (see ¶ [0072], [0059]).
However, Al-Qahtani does not teach: loaded with minoxidil and hydroxypropyl-β-cyclodextrin (claim 1’s limitation); or a bovine raw milk exosome (claims 2, 5, 8, 13, 16, and 28).
Gupta’s and Tamarkin’s teachings are discussed above and reprised herein (omitted herein for the sake of brevity).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load exosomes with a therapeutic agent such as taught by Gupta in the composition of Al-Qahtani. The ordinary artisan would have been motivated to do so is because of the reasons discussed above by the Gupta reference.
Furthermore, in regards to the claimed limitations of additional ingredients (e.g. hydroxypropyl-β-cyclodextrin (HPbCD), vitamins, methyl cellulose, other polymers), it would have secondly obvious to employ or use the additional adjuvants/excipients in the composition of Al-Qahtani-Gupta for the reasons discussed above by the Tamarkin reference.
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Claims 1-2, 4-9, 10-14, 16-18, and 27-29 are rejected under 35 U.S.C. 103 as being unpatentable over Gu (US 2021/0161968 A1) in view of Gupta (US 2016/0000710 A1 - cited in the IDS filed on 05/03/2023) and Tamarkin (US 2008/0260655 A1).
Gu’s general disclosure relates to methods and compositions for treating hair loss and/or promoting hair growth (see abstract & ¶ [0002], [0054], [0066], [0120]).
Gu teaches “a composition comprising: (a) a hydrophilic polymer network comprising keratin or a derivative thereof; (b) a natural product selected from the group comprising vesicles, stem cells, and vesicle-derived molecules, optionally wherein the vesicles are exosomes, further optionally wherein the natural product comprises mesenchymal stem cell (MSC)-derived exosomes; and (c) a small molecule hair growth agent” (see ¶ [0056], [0111]-[0115]).
Regarding minoxidil, Gu discloses the most common strategies for hair loss treatment include drug therapy, e.g., topical treatment with minoxidil (see ¶ [0053]). The small molecule hair growth agent comprises one or more selected from the group comprising minoxidil (see ¶ [0059]).
Regarding claim 10, Gu discloses “the exosome is an exosome isolated from mesenchymal stem cells (MSCs) or MSC-conditioned medium. The MSC can be derived from skin, bone marrow, gingiva, or another tissue. The exosomes (or other vesicles) can also be derived from tissue cells, such as, but not limited to, human adipose tissue” (see ¶ [0115]).
However, Gu does not teach: loaded with minoxidil and hydroxypropyl-β-cyclodextrin (claim 1’s limitation); or a bovine raw milk exosome (claims 2, 5, 8, 13, 16, and 28).
Gupta’s and Tamarkin’s teachings are discussed above and reprised herein (omitted herein for the sake of brevity).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to load exosomes with a therapeutic agent such as taught by Gupta in the composition of Gu. The ordinary artisan would have been motivated to do so is because of the reasons discussed above by the Gupta reference.
Furthermore, in regards to the claimed limitations of additional ingredients (e.g. hydroxypropyl-β-cyclodextrin (HPbCD), vitamins, methyl cellulose, other polymers), it would have secondly obvious to employ or use the additional adjuvants/excipients in the composition of Gu-Gupta for the reasons discussed above by the Tamarkin reference.
Examiner’s Response to Arguments
Applicant’s amendments and arguments filed on 10/31/2025 have been fully considered but they are not persuasive and deemed insufficient to overcome the prior arts of record.
(I) §103 Obviousness Rejections over Lim in view of Gupta and Tamarkin.
In response to Applicant’s argument (addressing pages 10-11 of the remarks) that “Lim does not teach or suggest: (1) bovine raw milk-derived exosomes, (2) exosomal encapsulation of minoxidil, (3) HPbCD as a component in exosomal formulations”: these arguments are not persuasive because “one cannot show non-obviousness by attacking references individually where the rejections are based on combinations of references … the test for obviousness is what the combined teachings of the references would have suggested to [a PHOSITA]” (MPEP 2145(IV)). As discussed in the prior office action, Lim first discloses that, for several decades, minoxidil has approved marketing for the treatment of hair loss; now arriving at the secondary reference of Gupta which cures these deficiencies of Lim because Gupta suggests that bovine milk exosomes can be loaded with a variety of therapeutic compounds and imply that said exosomes may have protective effects and anti-inflammatory activity than free therapeutic agents (see teaching-suggestion-motivation (TSM) by Gupta at ¶ [0124], [0132], [0134]). Thus, it is not considered unreasonable for an ordinary artisan to have envisage “an exosome loaded with minoxidil” because Lim discloses that minoxidil is a well-known approved first line therapy for the treatment of hair loss (see previous office action at page 7). Prior art is not limited just to the references being applied, but includes the understanding of one of ordinary skill in the art (MPEP 2141(III)).
In response to Applicant’s argument (addressing pages 10-11 of the remarks) that “Lim fails to disclose a process by which minoxidil is loaded into exosomes via passive diffusion in the presence of HPbCD. The claimed process [sic] describes the specific mechanism by which minoxidil enters the exosome membrane in the presence of HPbCD, enhancing drug bioavailability”: this argument is not persuasive because, as noted in the claim interpretation section above, the claimed invention, as a whole, is drawn to product (more specifically, a composition of matter). However, the claimed phrase of “loaded with minoxidil via a process that includes passive diffusion” invokes the interpretation of a product-by-process limitation but the determination of patentability is based on the product itself and does not depend on its method of production (MPEP 2113(I): Product-by-Process Claims). The MPEP 2113(II) further notes that “The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature than when a product is claimed in the conventional fashion”. Moreover, the arguments at length, allege that the prior art reference(s) has no discussion of their use in dermatological or hair growth applications thereby making them irrelevant to the claimed invention. In other words, Applicant’s remarks, drafting and language of the claims imply or infer a combination of three different/distinct categories of invention for examination analysis to include: (i) a product, (ii) a method of use, and (iii) a method of making, which renders it difficult to analyze to due to peculiar nature of the claims. “As a practical matter, the Patent Office is not equipped to manufacture products by the myriad of processes put before it and then obtain prior art products and make physical comparisons therewith” (MPEP 2113(III)).
In response to Applicant’s argument (addressing pages 11-12 of the remarks) that Gupta does not teach or suggest exosomes in a composition for treating hair loss, dermatological or hair growth applications: this argument is not persuasive for the reasons explained above. Again, it is first noted that base claim 1’s preamble of “for treating hair loss in a subject” has been considered but it is an intended use phrase that does not carry patentable weight (MPEP at 2111.02(II): Effect of the Preamble). The secondary reference of Gupta need not describe hair growth treatment because the primary reference of Lim had already stated this objective. Rather, Gupta was primarily relied upon to demonstrate that exosomes are well-known for the use as drug delivery applications. The nexus and reasonable expectation of success is because both of the references are directed to the use of exosomes and Gupta provides a methodology for exosome encapsulation or loading.
In response to Applicant’s argument (addressing pages 12-13 of the remarks) that Gupta lacks any discussion of cyclodextrin including HPbCD, does not describe passive diffusion, nor provides experimental data how encapsulating minoxidil in exosomes might alter its bioavailability or follicular penetration: these arguments are not persuasive because these are arguments against the references individually but obviousness is based upon a combination of references. Gupta was relied upon as a teaching suggestion motivation to load bovine exosomes with a therapeutic agent such as Lim’s minoxidil. The reference of Tamarkin teaches the HPbCD as stated in the prior office action on pages 7-8, bridging paragraph. Moreover, product-by-process limitations are not limited to its method of production via passive diffusion. Regarding the experimental data regarding how encapsulating minoxidil in exosomes improves its bioavailability or follicular penetration, as noted above, the instant specification does not mention these claimed terms and thus, comparison therewith of the prior art is difficult considering the product-by-process limitations.
In response to Applicant’s argument (addressing pages 13-14 of the remarks) that Gupta and Lim belong to distinct fields of use wherein Lim is directed to growth factor-based exosome therapy for hair growth and Gupta teaches exosomal drug delivery but no application to hair loss treatment: these arguments are not persuasive because both of the cited references are related to the use of exosomes and have the same field of classification. Moreover, it is not entirely clear if Applicant is implying that the claimed invention is different from Lim because “Instead, Lim’s exosomes work through the action of naturally occurring growth factors, such as HGF and VEGF”. Nevertheless, assuming arguendo, the claim’s transitional phrase of “comprising” is open-ended and does not exclude additional, unrecited elements such as Lim’s HGF or VEGF, and it appears the dependent claim 6 also allows for MSC secretome as additional active ingredients.
In response to Applicant’s argument (addressing pages 14-16 of the remarks) that “Tamarkin discloses HPbCD, but exclusively as a foam stabilizer, not as a drug loading agent for exosomes … which is irrelevant to the claimed invention’s use of HPbCD for enhancing minoxidil bioavailability and follicular penetration”: this argument is not persuasive for the reasons discussed above and in particular, due to the claim’s hybrid format of product-by-process limitations. Again, the patentability of a product does not depend on its method of production as the analysis is shifted to the mechanism of action and intended purpose of the process. Moreover, the reasoning to combine need not be the same as Applicant’s invention where the fact that Applicant has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. The guidelines for making the determination of obviousness provides examples of rationales that may support a conclusion of obviousness include: (a) combining prior art elements according to known methods to yield predictable results (MPEP 2141(III)). In particular, the primary reference of Lim teaches “the term “solubilizing agents” refers to those substances that enable solutes to dissolve. Representative examples of solubilizing agents that are usable include, without limitation, complex-forming solubilizers such as … cyclodextrin” (see Lim at ¶ [0200]). The disclosure of Tamarkin is general teaching of pharmaceutical compositions and manufacturing processes thereof to illustrate well-known ingredients and common practices within the purview of the ordinary artisan. HPbCD is a routinely employed to function as a stabilizing or solubilizing adjuvant agent to produce the desired viscosity dependent upon the desired topical formulation (e.g. gel, foam, cream, aerosol, etc.). Thus, HPbCD is known in the art for more than one purpose which does not need to be the same as Applicant’s reason. Furthermore, Tamarkin teaches examples of active agents include vitamin A, vitamin B, vitamin E (see Tamarkin at ¶ [0422]) and “skin bleaching and lightening agents (e.g., hydroquinone, kojic acid, ascorbic acid, magnesium ascorbyl phosphate, ascorbyl glucosamine), skin-conditioning agents (e.g., humectants, moisturizers, etc.), skin soothing and/or healing agents (e.g., panthenol and derivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and its derivatives, allantoin, bisabolol, and dipotassium glycyrrhizinate), skin treating agents, and vitamins and derivatives thereof” (see Tamarkin at ¶ [0456]-[0457]). These additional excipients are already known, well-established in the art, and routinely employed in the pharmaceutical arts.
In response to Applicant’s argument (addressing page 17 of the remarks) that the rejection fails to address the unpredictability of modifying exosomal formulations, which are complex biological systems with properties that cannot be readily inferred from general excipient disclosures: this argument is not persuasive because the prior office action at page 7 stated that “the ordinary artisan would have had a reasonable expectation of success is because both references are directed to the use of exosomes and Gupta provides a methodology for exosome encapsulation or loading”. Moreover, “The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion. Once the Examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an nonobvious difference between the claimed product and the prior art product”. Therefore, Applicant is invited to demonstrate the criticality of the additives or additional excipients and provide evidence as to why they would be unpredictable to incorporate.
In response to Applicant’s argument (addressing page 18 of the remarks) that the combination proposed is only logical in hindsight by improperly using Applicant’s disclosure as a roadmap to arrive at the claimed invention: it must be recognized that any judgment on obviousness is in a sense necessarily a reconstruction based upon hindsight reasoning. But so long as it takes into account only knowledge which was within the level of ordinary skill at the time the claimed invention was made, and does not include knowledge gleaned only from the applicant's disclosure, such a reconstruction is proper (MPEP 2145(X)(A)). In regards to Applicant’s argument that “However, the use of passive diffusion in the presence of HPbCD for enhanced exosomal penetration and bioavailability is not disclosed or suggested in the prior art”: this argument is not persuasive for the reasons maintained herein. The claimed invention, as a whole, is a product and not the “claimed process” and there does not appear to be any mention in the specification for the alleged point of novelty of “improved minoxidil bioavailability and enhanced follicular penetration compared to free minoxidil”. Applicant is invited to draw the Examiner’s attention to the specification for the finding of facts and comparative data for these claimed features.
In response to Applicant’s argument (addressing pages 19-20 of the remarks) that “the introduction of exogenous drug loading, such as minoxidil encapsulation, fundamentally shifts the function of Lim’s exosomes from a biological signaling tool to a drug delivery vehicle, contradicting Lim’s stated objective”: this argument is not persuasive because it is a rigid or narrow reading of the disclosure of Lim. The MPEP 2123 states that “A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art, including nonpreferred embodiments”. Lim is directed to the use of exosome to promote or enhance wound healing or hair growth (see Lim’s abstract & ¶ [0017]: Summary) and even provides an invitation to modify wherein “Other applications of the exosomes to promote hair growth will become readily apparent to one skilled in the art based upon the disclosure of this application and should be considered to be encompassed by the claims” (see Lim at ¶ [0071]). Said differently, the main objective of Lim is a hair loss treatment using exosomes and not limited to exclusively on the activity of growth factors. Thus, modifying Lim does not render the primary reference inoperable for its intended purpose.
In response to Applicant’s argument (addressing pages 20-21 of the remarks) that there is unpredictability and a lack of reasonable expectation of success: this argument is not persuasive for the reasons reprised from above. Due to the product-by-process claims, “The Patent Office bears a lesser burden of proof in making out a case of prima facie obviousness for product-by-process claims because of their peculiar nature" than when a product is claimed in the conventional fashion” (MPEP 2113(II)). Applicant may offer countering evidence that it is known in the art to be unsuccessfully attempted to demonstrate unpredictability.
In response to Applicant’s argument at length (addressing pages 22-35 of the remarks) that traverses obviousness rejections against the primary references of Levi, Al-Qahtani, and Gu: the Examiner’s responses from above may be made anew or reprised for these arguments because they are similarly applicable herein and not repeated for the sake of brevity.
Conclusion
No claims were allowed.
Applicant’s amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 extension fee 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 date of this final action.
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/NGHI V NGUYEN/Primary Examiner, Art Unit 1653