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
This application is a 371 of PCT/IB2020/061043 11/23/2020. Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. IN- 201911047906, filed on 11/22/2019. Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Status of Claims
Claims 1-11, and 27-29 are pending and under examination.
Response to Applicant’s Traversals
Examiner is presenting a new non-final rejection. All previous arguments from Applicant will be considered and addressed herein.
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.
Claim(s) 1-11, and 27-29 remain rejected under 35 U.S.C. 103 as being unpatentable over Young (KR 20170030830A, published March 20, 2017), in view of Srigiridhar (US 9,580,452 B2 , Issued February 28, 2017), in further view of Murphy (US 2009/0258841 A1, published October 15, 2009).
Young teaches a composition comprising esculetin, shown below.
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And further elucidates the mechanism and relevance of esculetin to the Applicant’s intent to treat various skin disorders using an esculetin derivative, by the following recitation:
“Another object of the present invention is to provide an antioxidant or anti-inflammatory external composition for skin comprising esculetin as an active ingredient.
In order to accomplish the above object, the present invention provides a skin external composition for preventing skin aging comprising esculetin represented by the following formula (1) as an active ingredient. The term "skin aging prevention" of the present invention means improvement of skin elasticity, skin moisturization, promotion of skin regeneration, or improvement of skin wrinkles. The present invention also provides an antioxidant or anti-inflammatory composition for external application for skin comprising esculetin represented by the following formula (1) as an active ingredient.”
In regards to Applicant’s argument that wound healing is not taught; Young recites the following:
“The present invention provides a skin external composition for preventing skin aging comprising esculetin as an active ingredient. The skin external composition for preventing skin aging may be used for improving skin elasticity, for moisturizing skin, for promoting skin regeneration, for improving skin wrinkles, but is not limited thereto. In addition, the composition for external application for skin has excellent skin regeneration ability and can be used for wound healing of skin surface.”
While Young is focused on aesthetic uses of the esculetin compound, there is sufficient overlap in the skin conditions of Young and the Applicant, such as skin regeneration, and skin wrinkles, further defined by the recitation:“The term "skin wrinkles" of the present invention refers to a scarring caused by skin degeneration, which may be caused by a cause of a gene, reduction of collagen present in the skin dermis, external environment, etc., and hyaluronic acid between elastin and collagen is reduced Skin wrinkles are created.”
Further background provided by Young:
“The functions of collagen present in the skin are known as mechanical rigidity of the skin, resistance of connective tissues and binding force of tissues, support of cell adhesion, induction of cell division and differentiation (when organism grows or healing) (van der Rest et al., 1990). Such collagen is related to regeneration of skin, elasticity of skin, prevention of aging of skin, wound healing, moisturization, and particularly, it is reduced by aging and photoaging by ultraviolet irradiation, and it is known to be closely related to wrinkling of skin (Arthur K "Aging and the Skin", 1989), and recent advances in extensive research on skin aging have revealed important functions of collagen in the skin.”
Young draws the nexus between the aesthetic applications of esculetin, (wrinkles, scarring, elasticity), and applications towards skin-regenerative purposes in general, (regeneration of skin, wound-healing), through collagen formation as a central acting mechanism induced by esculetin, further supported by Example 6 conducted by Young (See Page 5; Example 6).
Young teaches esculetin in a formulation for topical application (See Page 2; Description), as supported by the following recitation:
“More specifically, the formulation of the composition for external application for skin is a solution, an external ointment, a cream, a foam, a nutritional lotion, a soft lotion, a perfume, a pack, a soft water, a latex, a makeup base, an essence, Or a powder selected from the group consisting of sunflower oil, suspension, emulsion, paste, gel, lotion, powder, soap, surfactant-containing cleansing oil, powder foundation, emulsion foundation, wax foundation, patch, Can be used (See Page 4; Paragraph 5). The following paragraphs further provide pharmaceutically acceptable excipients, providing teaching, suggestion, and motivation to one skilled in the art, before the Applicant’s effective filing date, that esculetin would be of benefit for treatment of dermal conditions through topical administration.
Applicant previously states that Examiner acknowledges that Young “does not teach a composition with additional pharmaceutically acceptable excipients. This only means that Young does not use esculetin in the form of a topical formulation in the working examples demonstrating biological activity. This does not render a topical application of esculetin non-obvious, as there is, at least, teaching, suggestion, or motivation provided by Young to one skilled in the art by Young’s disclosure of topical formulations, before the Applicant’s effective filing date, to pursue applications of esculetin to dermal conditions through topical administration.
KSR Rationale – G requires: “Some Teaching, Suggestion, or Motivation in the Prior Art That Would Have Led One of Ordinary Skill To Modify the Prior Art Reference or To Combine Prior Art Reference Teachings To Arrive at the Claimed Invention” (MPEP 2143).
Further, Young does show working example of making a topical formulation of esculetin (see Page 6: Manufacturing example 1: Manufacture of nutritional cream). As previously mentioned, while this topical formulation was not used directly to evaluate biological activity, a working example in the prior art is not required to teach, suggest to, or motivate one skilled in the art to pursue that invention.
It is acknowledged by the examiner that Young does not teach a triphenyl phosphonium derivative of the esculetin. However, the presence of all the Applicant’s limitations within a single reference is not required under 35 USC § 103.
As recited above as a description of 35 USC § 103:
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.
In the instant case, Srigiridhar teaches the Applicant’s exact Formula (I) compound, including the triphenyl phosphonium addition, with the exact number carbon-chain (8) as a linker, as taught in claim 3, wherein X is defined as a carbon chain of 1 to 30 (See Page 8; Claim 3). Srigiridhar also teaches that by reducing oxidative activity in the mitochondria with esculetin as an active ingredient, an increase in collagen synthesis is observed as a result (See Page 7; Example 7).
Srigiridhar provides teaching, suggestion, or motivation to incorporate the triphenylphosphonium cation into the core esculetin structure of the Applicant’s compound, by the following recitation:
“Therefore, keeping in view of the involvement of mitochondrial ROS in causing endothelial dysfunction leading to the accentuation of vascular diseases, it would be ideal to counteract mitochondrial ROS by targeting ROS scavengers specifically to the site of action. The major drawback of antioxidant therapy in the treatment of mitochondrial diseases has been the inability to enhance antioxidant levels in mitochondria. Recently, there was a breakthrough in mitochondrial targeting of antioxidants (Drug delivery to mitochondria; the key to mitochondrial medicine. Adv Drug DelivRev. (2000) 41: 235-50). Antioxidants were covalently
coupled to a triphenylphosphonium cation (TPP), and these compounds were preferentially taken up by mitochondria (Selective targeting of a redox-active ubiquinone to mitochondria within cells; antioxidant and antiapoptotic properties. J Biol Chem. (2001) 276: 4588-4596). The lipophilic cations easily permeate through the lipid bilayers and subsequently build up several hundred-fold within mitochondria because of a large mitochondrial membrane potential. The uptake of lipophilic cations into the mitochondria increases 10-fold for every 61.5 mV difference in the membrane potential, leading to a 100- to 500-fold accumulation in mitochondria. This strategy not only reduces the concentration of the molecule that is being employed to scavenge ROS, but also reduces the nonspecific effects of the molecule if it were to be used at high concentrations to elicit a similar effect.”
This recitation directly establishes a current issue in the art, and how the addition of the triphenylphosphonium cation alleviates it (KSR Rationale – G. (MPEP 2143).
Applicant asserts that this does not provide teaching, suggestion, or motivation for how topical administration of the triphenylphosphonium – esculetin compound would exhibit enhanced activity, as Srigiridhar is silent on topical administration.
However, Srigiridhar elucidates two points relevant to one skilled in the art. The first is that the triphenylphosphonium cation addition to esculetin resulted in it being “preferentially taken up by mitochondria”. This is a matter of enhanced uptake in the mitochondria alone, absent of any considerations of pharmacokinetics (how much of the triphenylphosphonium – esculetin compound is absorbed either topically or orally). This would have one skilled in the art believe that once exposed to mitochondria, regardless of route of administration, the triphenylphosphonium – esculetin compound would be taken-up more efficiently than esculetin.
The second is that the lipophilic cations of the triphenylphosphonium – esculetin compound “can easily permeate through the lipid bilayers”. While Srigiridhar was referring to the lipid bilayers of the mitochondria originally, one skilled in the art would apply this principle to the lipid layers of skin, as lipophilic compounds are known to be absorbed by skin tissue.
Further supporting the idea to use a triphenylphosphonium - based antioxidant topically for skin regenerative purposes, Murphy teaches another antioxidant compound intended for topical application to skin, incorporating the triphenylphosphonium group with a carbon linker, in comparable fashion to the Applicant’s compound (See Page 2, Paragraph 0018), as shown below.
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Murphy further supports the previously introduced nexus between collagen formation and general skin-regenerative activity, and clarifies the role of antioxidant activity.
Murphy teaches that oxidative stress can lead to increased production of matrix metalloproteinases which degrade collagen in the skin (See Page 1; Paragraph 0008), as well as increasing the anti-oxidative activity in sites of reactive oxidative species (ROS) formation, such as keratinocyte and fibroblast mitochondria (See Page 2; Paragraph 0015) through administering antioxidants capable of penetrating into the mitochondria, and specifies the role of a lipophilic cationic moiety, wherein the moiety is capable of mitochondrially targeting the anti-oxidant moiety (See Page 2; Paragraph 0016), and wherein the moiety can be triphenylphosphonium as shown in the previous structure (See Page 5; Paragraph 00390).
Murphy also teaches that the compound can be used topically to promote wound healing (See Page 3; Paragraph 0023), psoriasis, ulcers (See Page 3; Paragraph 0022), pyoderma gangrenosum, and burns (See Page 7; Paragraph 0056).
Murphy provides teaching, suggestion, or motivation to one skilled in the art to incorporate a triphenylphosphonium group into an antioxidant compound, for enhanced uptake into mitochondria, and increased antioxidant activity leading to enhanced collagen formation, taught to be the driver of overall skin-regeneration.
Applicant argues that obtained results were unexpected, when Group 2, comprising 2.5% of esculetin, showed 0 out of 5 animals with wound healing, when compared to Group 5, comprising 2.5% of triphenylphosphonium – esculetin, showed 4 out of 5 animals with wound healing.
As discussed previously, this would not be unexpected to one skilled in the art, before the Applicant’s effective filing date, as there is teaching, suggestion, or motivation as to how the addition of triphenylphosphonium would enhance uptake of esculetin in mitochondria and is capable of being absorbed by skin tissue.
One in the art would expect comparable results to what the Applicant is claiming is unexpected, as the triphenylphosphonium addition to esculetin would enhance uptake into the mitochondria.
Regarding claims 27-29, please note where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed.) See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983). (“Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability…[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate.”)
In the instant case, Young, Srigiridhar, and Murphy provide adequate teaching, suggestion, or motivation to take the teachings of Young, laying the foundation for the mechanism of action of esculetin in promoting collagen synthesis, a mechanism explained to be foundational to skin tissue regeneration in both mild and aesthetic, as well as more intense and structural applications of skin conditions, as well as providing motivation to use esculetin in a formulation to be applied topically, and combine those teachings with those of Srigiridhar, elucidating the nexus between reducing mitochondrial oxidative stress, collagen synthesis, and skin-regeneration, and motivating one skilled in the art to modify esculetin with a triphenylphosphonium addition, in order to increased absorption into the mitochondria, as well as the teachings of Murphy, demonstrating the use of a triphenylphosphonium-based antioxidant being applied topically for skin-regenerative purposes through reducing oxidation in mitochondria and enhancing collagen synthesis, as well as disclosing a variety of skin conditions to be treated with this mechanism.
One having ordinary skill in the art would have been motivated, and have had reasonable expectation of success to combine the teachings and suggestions of Young, Srigiridhar, and Murphy before the Applicant’s effective filing date. Therefore, it would have been obvious to one having ordinary skill in the art, before the Applicant’s effective filing date, to combine these teachings and suggestions to develop a method of treating the variety of skin disorders and wounds claimed in the instant Application, by taking a known antioxidant such as esculetin, modifying it with a triphenylphosphonium attachment to further reach the mitochondria, and formulating it for topical application in a subject in need thereof.
Double Patenting
(The following Double Patenting rejection is necessitated by amendment)
The non-statutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A non-statutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on non-statutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a non-statutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
(Of Note: The following double patenting rejections are NON-PROVISIONAL)
Claims 27-29 are rejected on the ground of non-statutory double patenting as being unpatentable over the following claims of U.S. Patent No. US 9,580,452 B2 : 1 and 2 (for present claims 27-29.
Although the claims are not identical, they are not patentably distinct from one another because the claims of the co-pending application are also drawn to the same compound of the instant application. The ‘452 claims 1 and 2 are all drawn to the same compound and formulations thereof. The only difference between the Applicant’s kit comprising the compound, and the compound in claims 1 and 2 of ‘452, is that the Applicant’s kit requires instructions for use.
Please note where the only difference between a prior art product and a claimed product is printed matter that is not functionally related to the product, the content of the printed matter will not distinguish the claimed product from the prior art. In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004). (Claim at issue was a kit requiring instructions and a buffer agent. The Federal Circuit held that the claim was anticipated by a prior art reference that taught a kit that included instructions and a buffer agent, even though the content of the instructions differed.) See also In re Gulack, 703 F.2d 1381, 1385-86, 217 USPQ 401, 404 (Fed. Cir. 1983). (“Where the printed matter is not functionally related to the substrate, the printed matter will not distinguish the invention from the prior art in terms of patentability…[T]he critical question is whether there exists any new and unobvious functional relationship between the printed matter and the substrate.”)
It would have been prima facie obvious to one skilled in the art to arrive at the Applicant’s instant claims, in view of the claims of U.S. Patent No. US 9,580,452 B2 .
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to OROD MOTEVALLI whose telephone number is (571)272-6026. The examiner can normally be reached Monday - Friday 10:00AM - 6:00PM.
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/OROD MOTEVALLI/ Examiner, Art Unit 1628
/JARED BARSKY/ Primary Examiner, Art Unit 1628