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 .
Any rejection or objection from the previous office action, which is not restated here, is withdrawn.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 September 9, 2025, has been entered.
Election/Restrictions
Applicant’s election without traverse of Group I (i.e., claims 1, 3, 5-10, 17-18, 22-31, 39-43, 51, and 56 drawn to a method of treating or preventing a skin disease or disorder in a subject by administering one or more KEKTI protein domains) in the reply filed on April 13, 2023, is acknowledged. Additionally, Applicant’s election without traverse of Species A (i.e., a single and specific skin disease or disorder as pruritus); and Species B (i.e., a single and specific LEKTI protein domains as LEKTI domain 6 encoded by amino acid sequence SEQ ID NO: 109) in the reply filed on April 13, 2023, is acknowledged.
Please note that in light of the Examiner’s search, Species B is expanded to include where a microbe genetically modified to express the LEKTI protein domain 6 encoded by SPINK5 gene.
Status of Claims
Claims 1-58 were originally filed on November 4, 2020.
The amendment received on February 17, 2021, canceled claims 2, 4, 11-16, 19-21, 32-38, 44-50, and 52-55; and amended claims 1, 3, 5-10, 18, 23-24, 26-27, 29, 31, 39, 51, and 56. The amendment received on January 22, 2024, canceled claims 3, 5, 8, 17-18, and 22-31; amended claims 1, 6, 9-10, 40, 51, and 56; and added new claims 59-61. The amendment received on June 25, 2024, canceled claims 10, 39, and 59; amended claim 1, 40, and 60-61; and added new claim 62. The amendment received on June 25, 2024, canceled claims 6-7, 40-43, 51, and 62; and amended claim 1. The amendment received on September 9, 2025, amended claim 1; and added new claims 63-67.
Claims 1, 9, 56-58, 60-61, and 63-67 are currently pending and claims 1, 8, 41, 51, 56, 60-61 and 66 are under consideration as claims 57-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on April 13, 2023.
Please note that there are two new claim 65s. Instead of new claims 63-66, it should be new claims 63-67. As such, the Action will address the claim directed to measuring pruritus by an inhibition of TRP as new claim 66, and the claim directed to where the inhibition is at least 15% as new claim 67. However, it is respectfully requested that the claim numbering is corrected in response to this Action.
Priority
The present application claims the benefit under 35 U.S.C. 119(e) to U.S. Provisional Application No. 62/930,307 filed November 4, 2019; to U.S. Provisional Application No. 62/930,312 filed November 4, 2019; and to U.S. Provisional Application No. 62/930,313 filed November 4, 2019. Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) is acknowledged.
Claim Interpretation
For purposes of applying prior art, the claim scope has been interpreted as set forth below per the guidance set forth at MPEP § 2111. If Applicant disputes any interpretation set forth below, Applicant is invited to unambiguously identify any alleged misinterpretations or specialized definitions in the subsequent response to the instant action. Applicant is advised that a specialized definition should be properly supported and specifically identified (see, e.g., MPEP § 2111.01(IV), describing how Applicant may act as their own lexicographer).
For claim 1, regarding the scope of “treating” in a subject, it is noted that the instant specification defines “treating” as referring to clinical intervention in an attempt to alter the natural course of the subject or cell being treated (See instant specification, paragraph [0161]). Desirable effects of treatment include one or more of preventing occurrence or recurrence of disease, alleviation of symptoms, diminishment of any direct or indirect pathological consequences of the disease, stabilized state of disease, decreasing the rate of disease progression, amelioration or palliation of the disease state, prolonging survival as compared to expected survival if not receiving treatment and improved prognosis (See instant specification, paragraph [0161]). As such, the scope of “treating” one or more symptoms of pruritus encompasses prevention of pruritus to reduction of pruritus progression to alleviation of pruritus where the one or more symptoms itching, stinging, burning, tingling, tightness, erythema, and/or edema. However, the last wherein clause in claim 1 limits the treatment to “decreasing the one or more symptoms of pruritus”. Thus, the scope of claim 1 excludes 100% prevention of one or more symptoms of pruritus.
Regarding “a LEKTI protein domain”, it is noted that the instant specification teaches that LEKTI stands for lymphoepithelial kazal-type inhibitor and is a multi-domain serine protease inhibitor (See specification, paragraph [0009]). The LEKTI protein requires proteolytic cleavage for activation of its inhibitory function against many proteases (See specification, paragraph [0182]). The full length protein is cleaved into domains D1-D5 and D6-D15 where the D6-D15 domains are further cleaved in multiple steps into D6-D9 and D10-D15, [Wingdings font/0xE0]D6 and D7-D9 [Wingdings font/0xE0] D7 and D8-D9 [Wingdings font/0xE0] D8 (See specification, paragraph [0182]). As such, the instantly claimed one or more LEKTI protein domains encompass any combination of the 15 protein domains as long as one of the domains is LEKTI domain 6 (i.e., SEQ ID NO: 109).
Additionally, it is noted that the word “Kazal-type” in LEKTI is a known term in the art. Bitoun et al. identified SPINK5 (serine protease inhibitor Kazal-type 5) as the defective gene in Netherton syndrome (NS) where a total of 34 SPINK5 mutations have been reported in patients (See Bitoun et al., Human Molec. Genet. 12:2417-2430 (2003) at pg. 2418, col. 1, 2nd paragraph). Bitoun et al. also teaches that SPINK5 encodes LEKTI (lympho-epithelial Kazal-type related inhibitor), which is a predicted serine protease inhibitor (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). The protein consists of 1064 amino acids organized into 15 potential inhibitory Kazal-type domains (D1-D15) (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). Only D2 and D15 perfectly match the typical Kazal motif [C-(X)n-C-(X)7-C-(X)10-C-(X)2/3-C-(X)m-C], whereas the other domains exhibit a Kazal-type-derived four cysteine residue pattern (See Bitoun article, pg. 2418, col. 1, 2nd paragraph). Thus, an ordinary skilled artisan would be well aware of what is referred to as a “Kazal-type”.
Additionally, regarding “pruritus” and “itching”, it is noted that the instant specification defines “pruritus” and “itch” as interchangeable referring to an unpleasant cutaneous sensation which provokes the desire to scratch (See instant specification, paragraph [0150]).
Sequence Interpretation
For claim 60, please note that the Examiner is interpreting the scope of claim 60 as open-ended requiring 90% identity to SEQ ID NO: 109 with any N-/C-terminal additions. It is noted that the amino acid sequence of the LEKTI domain 6 encompasses up to 6 amino acid modifications including deletions, substitutions, and/or additions not at the N-C-termini.
For claim 61, please note that the Examiner is interpreting the scope of claim 61 as closed-ended requiring 100% identity and the same length to SEQ ID NO: 109.
Response to Arguments
Applicant’s arguments, see Response, filed 9/9/25, with respect to the 103(a) rejection have been fully considered and are persuasive. The rejection of claims 1, 56, and 60-61 as being unpatentable over Whitfill et al. US Publication No. 2019/0040116 A1 published on February 7, 2019, in view of Medline Plus, “Netherton syndrome,” Natl. Library Med., available online at https://medlineplus.gov/genetics/condition/netherton-syndrome/, 4 pages (2014) has been withdrawn.
New Objections
Claim Objections
Claims 63-64 are objected to because of the following informalities: claim 63 recites “TRVP1” and claim 64 recites “TRVP4”. It is respectfully requested that claim 63 recites “TRPV1” and claim 64 recites “TRPV4” in order to be grammatically correct. Appropriate correction is required.
New Rejections
Claim Rejections - 35 USC § 112
The following is a quotation 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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
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 of carrying out his invention.
Claim 67 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a new matter rejection.
In the instant case, claim 67 was added (cf. amendment filed 9/9/2025) to further limit new claim 66, and is directed to where the inhibition is at least 15% compared to an untreated control. It is noted that “at least 15%” does not have an upper limit thereby encompassing up to 100% or complete inhibition. Applicants stated in their remarks that “[n]o new matter has been added.” (See pg. 4 of the Remarks filed on 9/9/2025). However, the specification-as-filed and original claims do not support that the full scope of the claimed inhibition percentage range of claim 67 was previously presented as the there is no indication either expressly or inherently that the LEKTI domain 6 exhibited an inhibition percentage above 56.4% +/-16% for TRPV1 and above 73% +/- 10.8% for TRPV4.
Lack of Ipsis Verbis Support
The specification is void of support that would clearly support the newly added claim. The specification does not teach the specifically claimed method of treating one or more symptoms of pruritus in a subject by administering a microbe genetically modified to express LEKTI protein domain 6 to the skin of the subject where the treatment of pruritus is measured by an inhibition of at least 15% of a TRP channel associated with itch compared to an untreated control. Examination of the instant support shows in Example 9 that when LEKTI protein domain 6 is added in vitro to TRPV1 or TRPV4 cells at a range of concentrations (See instant, [0472]-[0475]). For TRPV1, the mean % inhibition when LEKTI protein domain 6 is added ranged from a negative amount (i.e., -4.0 and – 11.1) thereby encompassing no inhibition at a concentration of 0.003 or 0.03 µM up to a mean % inhibition of 56.4% at a concentration of 3 µM (See instant, [0478]). For TRPV4, the mean % inhibition when LEKTI protein domain 6 is added ranged from a negative amount (i.e., -24.1 and -11.0) thereby encompassing no inhibition at a concentration of 0.003 or 0.01 µM up to a mean % inhibition of 73.0% at a concentration of 10 µM (See instant, [0480]). As such, the percent inhibition range is dependent upon the TRP channel. Moreover, neither percent inhibition range spans the entire claimed range. Positive recitation of specific inhibition percentages without any indication of the claimed full percentage range does not provide support in claiming that the inhibition is at least 15% compared to an untreated control. Pursuant to MPEP 2163.03(V), [a]n original claim may lack written description support when . . . (2) a broad genus claim is presented but the disclosure only describes a narrow species with no evidence that the genus is contemplated. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1349-50 (Fed. Cir. 2010) (en banc). "Even if a claim is supported by the specification, the language of the specification, to the extent possible, must describe the claimed invention so that one skilled in the art can recognize what is claimed. The appearance of mere indistinct words in a specification or a claim, even an original claim, does not necessarily satisfy that requirement. "Enzo Biochem, Inc. v. Gen-Probe, Inc., 323 F.3d 956, 968, 63 USPQ2d 1609, 1616 (Fed. Cir. 2002). Therefore, the claimed inhibition range of “at least 15%” is not expressly described.
Lack of Inherent Support
“While there is no in haec verba requirement, newly added claim limitations must be supported in the specification through express, implicit, or inherent disclosure.” MPEP 2105 states that “[a] lack of adequate written description issue also arises if the knowledge and level of skill in the art would not permit one skilled in the art to immediately envisage the product claimed from the disclosed process. See, e.g., Fujikawa v. Wattanasin, 93 F.3d 1559, 1571, 39 USPQ2d 1895, 1905 (Fed. Cir. 1996) (a "laundry list” disclosure of every possible moiety does not constitute a written description of every species in a genus because it would not “reasonable lead” those skilled in the art to any particular species); In re Ruschig, 379 F.2d 990, 995, 154 USPQ 118, 123 (CCPA 1967). In the instant case, as set forth above, the disclosure describes a specific inhibition range for TRPV1 and a specific inhibition range for TRPV4. (See instant, Example 9). However, the instantly claimed genus encompassing inhibition of at least 15% has not been adequately supported.
Claim Rejections - 35 USC § 103
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under pre-AIA 35 U.S.C. 103(a) 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 under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
103 - KSR Examples of 'Rationales' Supporting a Conclusion of Obviousness(Consistent with the "Functional Approach" of Graham)
Further regarding 35 USC 103(a) rejections, the Supreme Court in KSR International Co. v. Teleflex Inc., 550 U.S. 398, 127 S. Ct. 1727, 82 USPQ2d 1385, 1395-97 (2007) (KSR) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. The key to supporting any rejection under 35 U.S.C. 103 is the clear articulation of the reason(s) why the claimed invention would have been obvious. The Supreme Court in KSR noted that the analysis supporting a rejection under 35 U.S.C. 103 should be made explicit.
Exemplary 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;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" - choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) 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.
Note that the list of rationales provided is not intended to be an all-inclusive list. Other rationales to support a conclusion of obviousness may be relied upon by Office personnel.
Also, a reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976).
Claims 1, 56, 60-61, and 64-67 are rejected under 35 U.S.C. 103 as being unpatentable over Whitfill et al. US Publication No. 2019/0040116 A1 published on February 7, 2019, in view of Lee et al., Yonsei Med. J. 51:808-822 (2010).
NOTE: Although the Applicant is the same for both the instant application and ‘116 publication, the inventors are different. As such, the 102(b)(1)(A) exception does not apply without evidence to the contrary.
For claims 1, 60-61, and 63-65, with respect to a method of treating one or more symptoms of pruritus in a subject in need thereof where the one or more symptoms comprises itch, by administering a microbe genetically modified to express LEKTI domain 6 to the skin of the subject where the LEKTI protein domain 6 is a TRP channel antagonist and where the LEKTI protein domain 6 decreases the one or more symptoms of pruritus as recited in instant claim 1; with respect to where the at least one LEKTI domain comprises at least 90% identity to SEQ ID NO: 109 as recited in instant claim 60; with respect to where the at least one LEKTI domain consists of SEQ ID NO: 109 as recited in instant claim 61; with respect to where the TRP channel is TRPV1 as recited in instant claim 63; and with respect to where the TRP channel is TRPV4 as recited in instant claim 64; and where the one or more symptoms of pruritic are a result of TRP channel activity as recited in instant claim 65:
Whitfill et al. claims a method of treating or ameliorating the effects of a skin disease of a mammal in need thereof by providing onto a surface of the skin of the mammal a microbe genetically modified to express one or more LEKTI protein domains wherein the LEKTI protein domains are effective to penetrate one or more layers of the mammal’s skin and effective to inhibit activity of at least one serine protease in or on the mammal’s skin (See Whitfill specification, claim 14; paragraph [0020], [0073]). Whitfill et al. defines “treating” as providing to a subject a protocol, regimen, process or remedy, in which it is desired to obtain a physiologic response or outcome in that subject (See Whitfill specification, paragraph [0041]), and “ameliorating” as decreasing the severity of the symptoms of a disease in a subject (See Whitfill specification, paragraph [0055]). Moreover, Whitfill et al. discloses that a “skin disease” is defined as a skin state or condition that is generally undesirable or deleterious compared to the normal or baseline condition of human skin (See Whitfill specification, paragraph [0039]). As such, the Whitfill method encompasses treating or ameliorating a symptom as an effect of a skin disease of a mammal (i.e., a subject) thereby providing a therapeutic effect to decrease the skin disease. Whitfill et al. also defines “genetically modified” as a microbial organism that has been genetically modified or engineered by the introduction of DNA prepared outside the microbe (See Whitfill specification, paragraph [0040]). As such, the genetically modified microbe in Whitfill’s claim is a microbe containing DNA encoding the one or more LEKTI protein domains. Furthermore, Whitfill et al. teaches that the SPINK5 (serine protease inhibitor of kazal type 5) gene encodes the LEKTI protein (See Whitfill specification, paragraph [0007]). Therefore, Whitfill et al. suggests that the SPINK5 gene can be used as the DNA that encodes the one or more LEKTI protein domains thereby constituting where the microbe is genetically modified. Thus, the method taught by Whitfill et al. is directed to ameliorating a symptom of a skin disease in a mammal by providing onto a surface of the skin of the mammal a microbe genetically modified to express one or more LEKTI protein domains where the one or more LEKTI protein domains provide a therapeutic effect to decrease the skin disease as recited in instant claim 1.
Regarding the genetically modified microbe expressing LEKTI protein domain 6, Whitfill et al. teaches that the full-length LEKTI protein contains 15 inhibitory domains, D1-D15 (See Whitfill specification, paragraph [0007]). Whitfill et al. also teaches that the LEKTI domain to be administered is domain 6 (See Whitfill specification, paragraph [0052], [0054], [0156]). The amino acid sequence of the LEKTI domain 6 is depicted as SEQ ID NO: 109, which is 100% identical and the same length to instant SEQ ID NO: 109. Moreover, Whitfill et al. demonstrates that the LEKTI domain 6 exhibits inhibition of kallikrein-related peptidases (KLK), in particular, kallikrein 5 and 7 thereby demonstrating trypsin inhibition (See Whitfill specification, paragraph [0156]-[0158]). Whitfill et al. also teaches that various LEKTI inhibitory fragments can inhibit various kallikrein-related peptidases such as KLK5, 7, and 14 (See Whitfill specification, paragraph [0009]). LEKTI deficiency or defective LEKTI can then result in deregulated protease activity causing skin desquamation and epidermal permeability through impaired epidermal differentiation and lipid metabolism thereby leading to a defective skin barrier (See Whitfill specification, paragraph [0010]). Plus, unregulated activity of some KLK proteins leads to desmosome cleavage and stratum corneum detachment (See Whitfill specification, paragraph [0010]). Thus, Whitfill et al. suggests that the LEKTI protein domain to be expressed by the microbe is LEKTI domain 6 having or consisting of the amino acid sequence of SEQ ID NO: 109 as recited in instant claims 1 and 60-61 where this LEKTI domain 6 functions as an inhibitor of KLK5 and 7.
Regarding where the symptom to be treated is pruritus/itch and where the LEKTI protein domain 6 is a TRP channel antagonist, Whitfill et al. teaches examples of an abnormal skin condition to be treated or ameliorated is Netherton Syndrome (NS), psoriasis, acne, atopic dermatitis (AD) allergic contact dermatitis, epidermolytic hyperkeratosis, seborrheic dermatitis, eczema, dry skin, allergy, rashes, etc. (See Whitfill specification, paragraph [0039]). As such, the teachings of Whitfill et al. suggest a method ameliorating a symptom of AD in a mammal by providing onto a surface of the skin of the mammal a microbe genetically modified to express LEKTI protein domain 6 that functions as a serine protease inhibitor including inhibition of kallikreins 5 and 7 where the LEKTI protein domain 6 provides a therapeutic effect to decrease the skin disease as recited in instant claim 1.
However, Whitfill et al. does not expressly teach that a symptom of AD to be treated or ameliorated is pruritus or itch as a result of TRP channel activity, and does not expressly teach that the LEKTI protein domain 6 is a TRP channel antagonist of TRPV1 or TRPV4.
Lee et al. teaches that proteases in the skin are essential to epidermal permeability barrier homeostasis (See Lee, abstract; pg. 808, last paragraph). In the skin, three families of proteases have been found in the stratum corneum (SC) including the epidermal specific serine proteases, KLK5 and KLK7 (See Lee, pg. 808, last paragraph). These proteases are tightly regulated by specific protease inhibitors and mediate various cellular responses in the skin (See Lee, pg. 809, col. 1, 1st paragraph). A number of biological activities of proteases are mediated, at least in part, by the activation of its receptors, protease-activated receptors (PARs) (See Lee, abstract; pg. 809, col. 1, 1st paragraph). PAR-2 plays numerous physiological and pathophysiological roles in the skin including pruritus (See Lee, abstract; pg. 809, col. 1, 1st paragraph). Lee et al. also teaches that abnormal expression or activity of serine proteases and PAR-2 has been associated with several inflammatory skin disorders involving barrier abnormalities including AD, NS, psoriasis, and peeling skin syndrome (See Lee, pg. 809, col. 1, 1st paragraph). Lee et al. sought to review the role of protease/PAR-2 signaling in epidermal permeability barrier homeostasis and its contribution to the pathogenesis of AD (See Lee, pg. 809, col. 1, 1st paragraph).
Furthermore, Lee et al. teaches that it is well known that KLK5 and KLK7 are the major active KLKs in the SC, regulating the desquamation process through corneodesmosomal cleavage and lipid barrier formation by degrading lipid processing enzymes (See Lee, pg. 809, col. 1, last paragraph). KLK5 and KLK7 are stored in the form of proenzyme in the lamellar bodies (LBs) along with a substrate of KLK7, corneodesmosin and their inhibitor, lymphoepithelial Kazal-type-related inhibitor (LEKTI) (See Lee, pg. 809, col. 1, last paragraph). KLK5 is thought to be the key protease for the initiation of the KLK cascade and involved in PAR-2 activation (See Lee, pg. 809, col. 2, 1st paragraph; pg. 810, col. 2, last paragraph; pg. 812, col. 1, 2nd paragraph). Significantly, KLK5 and KLK14 are known to activate PAR-2, thereby modulating epidermal permeability barrier homeostasis, immune and inflammatory responses, skin pigmentation, itching sensations, as well as tumor surveillance (See Lee, pg. 809, col. 2, 1st paragraph) (emphasis added). Among others, LEKTI-1, a secreted serine protease inhibitor, is thought to be the major player in the SC, which exhibits diverse inhibitory effects toward trypsin (See Lee, pg. 809, col. 2, last paragraph). In addition, previous in vitro studies demonstrated that LEKTI fragments could inhibit KLK5, -6, -7, -13, and -14 (See Lee, pg. 809, col. 2, last paragraph to pg. 810, col. 1, 1st paragraph). The interaction strength between LEKTI-1 and KLKs is regulated by the SC pH gradient, with its highest inhibitory capacity at a neutral pH and decreased activity in an acidic pH environment (See Lee, pg. 810, col. 1, 1st paragraph). It is well known that KLKs, especially KLK5 and KLK7, act as main players in desquamation through a pH dependent protease signaling cascade (See Lee, pg. 812, col. 1, 2nd paragraph; Fig. 1). As depicted in Fig. 2, a reduction of LEKTI results in an increase in KLK5, 7, and 14, which in turn results in activation of PAR-2, and which in turn leads to AD-like lesions (See Lee, pg. 813, col. 2, last paragraph; Fig. 2). Inhibition of PAR-2 activation, by topical application of either serine protease inhibitor or PAR-2 specific antagonist significantly accelerated the barrier recovery rate after acute barrier disruption (See Lee, pg. 813, col. 2, last paragraph to pg. 814, 1st paragraph). These findings support the fact that AD, characterized by altered skin surface pH, and NS, characterized by genetically defective LEKTI, display similar phenotypic features, including premature and excessive desquamation (See Lee, pg. 810, col. 1, 1st paragraph).
Lee et al. teaches that AD is a multifactorial inflammatory skin disease characterized by genetic barrier defects and allergic inflammation (See Lee, abstract). Recent studies have revealed aberrant expression and activation of serine proteases and PAR-2 in the lesional skin of AD patients (See Lee, abstract; pg. 815, col. 1, 1st paragraph). Skin nerve fibers are known to have functional PAR-2 where it has been proposed that PAR-2 plays an important role in pruritus (See Lee, pg. 814, col. 2, last paragraph to pg. 815, col. 1, 1st paragraph). PAR-2 signaling also stimulates the release of neuropeptides from central nerve endings at the spinal cord level thereby activating CGRP receptor and SP receptor (NK1R) to transmit itch responses to the central nervous system (See Lee, pg. 815, col. 1, 1st paragraph). One recent study reported that the mice that over-expressed epidermal KLK7 displayed massive itchy behavior (See Lee, pg. 815, col. 1, 1st paragraph). Another study demonstrated that trypsin-induced scratching behavior in mice was inhibited by a PAR-2 blocking peptide, suggesting the role of serine protease/ PAR-2 signaling in pruritus (See Lee, pg. 815, col. 1, 1st paragraph). Moreover, PAR-2 activation is likely to be involved in pruritus of AD where PAR-2 agonist peptide induced pruritus in AD patients (See Lee, pg. 815, col. 1, 1st paragraph). In addition, the fact that KLK5, -7, -8, and -14 are present in sweat, (sweat being the most common itch-triggering factor in AD) point to the important role of PAR-2 in pruritus of AD patients (See Lee, pg. 815, col. 1, 1st paragraph). Plus, Lee et al. teaches that PAR-2 is reported to interact synergistically with transient receptor potential (TRP) vanilloid-type 1 (TRPV1), which belongs to the superfamily of TRP channels, thereby amplifying itch sensation (See Lee, pg. 815, col. 1, 1st paragraph). As such, Lee et al. teaches that the imbalance between proteases and protease inhibitors associated with genetic defects in the protease/protease inhibitor encoding genes, increase in the skin surface pH, and exposure to proteolytically active allergens contribute to this aberrant protease/PAR-2 signaling in AD (See Lee, abstract). The increased protease activity in AD leads to abnormal desquamation, degradation of lipid-processing enzymes and antimicrobial peptides, and activation of primary cytokines, thereby leading to permeability barrier dysfunction, inflammation, and defects in the antimicrobial barrier (See Lee, abstract). Moreover, up-regulated proteases stimulate PAR-2 in lesional skin of AD and lead to the production of cytokines and chemokines involved in inflammation and immune responses, itching sensation, and sustained epidermal barrier perturbation with easier allergen penetration (See Lee, abstract). These findings suggest that serine protease inhibitors or PAR-2 antagonists might be a promising therapeutic tool for the management of itching and help break the vicious itch-scratch cycle in AD (See Lee, pg. 815, col. 1, 1st paragraph). Although drawbacks are noted, one means of addressing AD and the symptoms associated with AD such as pruritus or itch would be applying topical protease inhibitors (See Lee, pg. 817, col. 2, 2nd paragraph). Thus, Lee et al. suggests a cascade pathway leading to AD and the AD symptom of pruritus/itch where this pathway involves LEKTI as a key inhibitor such that LEKTI dysfunction would result in increase in KLK5, 7, and 14 expression, which in turn activates PAR-2, which works synergistically with TRPV1 to amplify itch sensation in AD patients. Therefore, the combination of Whitfill et al. suggests that treatment of AD and its symptoms such as pruritus with topical administration of a serine protease inhibitor such as the LEKTI protein domain 6 that would inhibit KLK5 and 7 expression thereby indirectly inhibiting PAR-2 activation and precluding the synergistic interaction between PAR-2 and TRPV1 whereby such downstream inhibition reduces pruritus in AD patients.
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the instant application to modify the teachings of Whitfill et al. and topically administer a microbe that is genetically modified to express the LEKTI protein domain 6 having the amino acid sequence of SEQ ID NO: 109 onto the skin of a mammal suffering from AD in order to treat or ameliorate pruritus/itch as a symptom of AD by directly inhibiting KLK5 and 7 expression and indirectly inhibiting PAR-2 activation thereby precluding the synergistic interaction between PAR-2 and TRPV1 via the direct inhibition of KLK5 and 7 whereby the indirect inhibition reduces pruritus, in part by TRP channel activity, in AD patients . One of ordinary skill in the art at the time the invention was made would have been motivated to do so because LEKTI protein domain 6 having the amino acid sequence of SEQ ID NO: 109 was known to treat a skin disease by inhibiting KLK5 and 7 as serine proteases as taught by Whitfill et al.; and because pruritus/itch in AD was known to be induced by the cascade pathway initiated by KLK5 due to LEKTI dysfunction and/or pH imbalance where KLK5 expression activates PAR-2 known to induce itch and known to then synergistically interact with TRPV1 thereby amplifying itch, and where one treatment of AD and its symptoms such as pruritus were known to include administration of a serine protease inhibitor as taught by Lee et al. One of ordinary skill in the art at the time the invention was made would have had a reasonable expectation of success given that the microbe of Whitfill et al. was used to treat or ameliorate a symptom of AD in a mammal via topical administration onto the mammal’s skin, and therefore, topically administering a microbe genetically modified to express the LEKTI protein domain 6 having the amino acid sequence of SEQ ID NO: 109 would support the treatment or amelioration of AD and its symptoms including pruritus/itch in the mammal by directly inhibiting KLK5 and 7 expression and indirectly inhibiting PAR-2 activation thereby precluding the synergistic interaction between PAR-2 and TRPV1 via the direct inhibition of KLK5 and 7 whereby the indirect inhibition reduces pruritus, in part by TRP channel activity, in AD patients by constituting by constituting 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 pursuant to KSR.
Additionally and/or alternatively, regarding the LEKTI protein domain 6 functioning as a TRP channel antagonist, and in particular, a TRPV1 and TRPV4 antagonist, it is noted that the scope of claims 1 and 63-64 do not require that the LEKTI protein domain 6 functions directly as a TRPV1/4 antagonist. Rather, indirect inhibition is encompassed. Thus, the combined teachings of Whitfill et al. and Lee et al. suggest that the LEKTI protein domain 6 is an indirect TRPV1 antagonist. However, since Whitfill et al. expressly teaches a genetically modified microbe expressing the LEKTI protein domain 6 thereby constituting a known product, but does not expressly teach that , the functional properties (i.e., TRP channel antagonism as recited in instant claim 1 where the TRP channel is TRPV1 as recited in instant claim 63 or TRPV4 as recited in instant claim 64) of the product as claimed and the known product would necessarily read upon the same. The discovery of a previously unappreciated property of a prior art composition, or a scientific explanation for the prior art’s functioning, does not render the old composition patentably new to the discoverer. Atlas Powder Co. v. Ireco Inc., 190 F.3d 1342, 1347, 51 USPQ2d 1943, 1947 (Fed. Cir. 1999). Thus, the claiming of new functional properties (i.e., TRP channel antagonism as recited in instant claim 1 where the TRP channel is TRPV1 as recited in instant claim 63 or TRPV4 as recited in instant claim 64) which would necessarily read upon the prior art does not necessarily make the claim patentable. In re Best, 562 F.2d 1252, 1254, 195 USPQ 430, 4333 (CCPA 1977). Thus, the combination of Whitfill et al. and Lee et al. render claims 1 and 63-65 obvious.
For claim 1, with respect to where the genetically modified microbe is topically administered to the subject:
As discussed supra, Whitfill et al. claims a method of treating or ameliorating the effects of a skin disease of a mammal in need thereof by providing onto a surface of the skin of the mammal a microbe genetically modified to express one or more LEKTI protein domains. As such, Whitfill expressly claims that the genetically modified microbe is topically administered to a subject. Moreover, Whitfill et al. teaches that the genetically modified microbe is formulated as a topical formulation in any form suitable for application to the body surface such as a cream, lotion, sprays, solution, gel, ointment, paste, plaster, paint, bioadhesive, suspensions, emulsions or the like, and/or can be prepared so as to contain liposomes, micelles and/or microspheres (See Whitfill specification, paragraph [0081]). Therefore, the teachings of Whitfill et al. satisfy the claim limitation with respect to where the genetically modified microbe is administered topically to the subject as recited in instant claim 1.
For claim 56, with respect to where the microbe is Acinetobacter spp., Corynebacterium spp., Pseudomonas spp., Staphylococcus spp., etc.:
Whitfill et al. teaches that the examples of microbes that are genetically modified to express the one or more LEKTI protein domains are non-pathogenic and commensal bacteria such as Staphylococcus epidermidis or warneri, Streptococcus pyrogenes or mitis, or Acinetobacter johnsonii (See Whitfill specification, paragraph [0025]-[0026], [0045]-[0046], [0049], [0071]). Therefore, the teachings of Whitfill et al. satisfy the claim limitation as recited in instant claim 56.
For claims 66-67, with respect to where the treatment of pruritus is measured by an inhibition of a TRP channel associated with itch compared to an untreated control as recited in instant claim 66; and with respect to where the inhibition is at least 15% compared to an untreated control as recited in instant claim 67:
Whitfill et al. and Lee et al. do not expressly compare the treatment of pruritus via measurement of the level of TRP channel inhibition by a microbe genetically modified to express LEKTI protein domain 6 when compared to an untreated control where the amount of inhibition is at least 15% compared to the untreated control.
MPEP 2112-2112.02 states that when a reference discloses all the limitations of a claim except for a property or function, and the examiner cannot determine whether or not the reference inherently possesses properties which render obvious the claimed invention but has basis for shifting the burden of proof to applicant as in In re Fitzgerald, 619 F.2d 67, 205 USPQ 594 (CCPA 1980). In the instant case, as discussed supra, Whitfill et al. teaches topically administering a microbe genetically modified to express the LEKTI protein domain 6 having the amino acid sequence of SEQ ID NO: 109 where the LEKTI protein domain 6 functions as a serine protease inhibitor against KLK5 and 7 in order to treat or ameliorate a skin disease and its symptoms such as AD. Lee et al. further demonstrates that the LEKTI protein domain 6 functioning as a serine protease inhibitor against KLK5 and 7 indirectly inhibits PAR-2 activation thereby precluding the synergistic interaction between PAR-2 and TRPV1 thereby decreases itching as a symptom of pruritus in AD patients.
The Patent and Trademark Office is not equipped to conduct experimentation in order to determine whether or not applicants’ treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 differs in its measured TRP channel inhibition when compared to an untreated control, and if so to what extent, from the treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 via its indirect downstream inhibition of TRP channel activity taught in Whitfill et al. and Lee et al. The cited art taken as a whole demonstrates a reasonable probability that the treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 of Whitfill et al. in view of Lee et al. is either identical or sufficiently similar to the claimed treatment of pruritus by the microbe genetically modified to express LEKTI protein domain 6 that whatever differences exist are not patentably significant. Therefore, with the showing of the reference, the burden of establishing non-obviousness by objective evidence is shifted to the Applicants.
Merely because an intended result of a treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6, i.e., treatment of pruritus via measurement of TRP channel inhibition relative to an untreated control where the TRP channel inhibition is at least 15% relative to the untreated control, is not expressly taught in a reference does not make the known method of using a known product patentable. The treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 possesses properties necessarily present which might not be displayed in the tests used in Whitfill et al. and Lee et al. Accordingly, the disclosure of Whitfill et al. in view of Lee et al. is a sufficient basis that the treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 via its indirect downstream inhibition of TRP channel activity would result in the treatment of pruritus by measuring a TRP channel inhibition level of at least 15% when compared to an untreated control.
In the alternative, even if the claimed treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 via a measured TRP channel inhibition level of at least 15% relative to an untreated control is not identical to Whitfill and Lee’s treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 via its indirect downstream inhibition of TRP channel activity with regard to some unidentified properties, the differences between that which is taught and that which is claimed are considered to be so slight that Whitfill and Lee’s treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 is likely to inherently possess the same properties of the claimed treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6, particularly in view of the similar structural characteristics, similar manipulative step of administration, and similar patient population to be treated. Thus, the claimed treatment of pruritus by a microbe genetically modified to express LEKTI protein domain 6 via a measured TRP channel inhibition level of at least 15% relative to an untreated control would have been obvious to those of ordinary skill in the art under the meaning of USC 103. Accordingly, the claimed invention as a whole was at least prima facie obvious, especially in the absence of sufficient, clear, and convincing evidence to the contrary.
Response to Arguments
Applicant’s arguments with respect to claims 1, 56, 60-61, and 63-64 have been considered but are moot as the new rejection utilizes a different rationale for rendering the claimed invention obvious. However, Applicants’ arguments as they pertain to the rejection supra.
In response to Applicant’s argument that the prior art references fail to teach or suggest all the claim limitations because the Whitfill reference fails to treat or suggest treating one or more symptoms of pruritus in a subject where the symptom is itch, it is found unpersuasive. As stated in the Actions mailed on 8/14/24 and 5/9/25, it is acknowledged that there is not a single reference that teaches and/or suggests every claim limitation recited in instant claim 1 and the dependent claims. However, Applicants are respectfully reminded that the rejection supra are based on obviousness. Pursuant to MPEP 2142, 35 USC 103 authorizes a rejection where, to meet the claim, it is necessary to modify a single reference or to combine it with one or more other references (emphasis added). Since the rejection is based on obviousness, it is unnecessary for every claim limitation to be taught and/or suggested by a single reference. Furthermore, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007). In the instant case, as discussed in the rejection supra, Whitfill et al. expressly teaches administering a microbe genetically modified to express LEKTI protein domain 6 encoded by a SPINK5 gene to the skin of a mammal in order to treat a skin disease such as AD. The genetically modified microbe can be formulated as a topical formulation in any form suitable for application to the body surface such as a cream, lotion, sprays, solution, gel, ointment, paste, plaster, paint, bioadhesive, suspensions, emulsions or the like, and/or can be prepared so as to contain liposomes, micelles and/or microspheres (See Whitfill specification, paragraph [0081]). As such, Whitfill expressly teaches administering the genetically modified microbe topically. Moreover, as discussed in the rejection supra, Whitfill expressly defines “ameliorating” as decreasing the severity of the symptoms of a disease in a subject. Whitfill also expressly demonstrates that LEKTI protein domain 6 inhibits KLK5 and 7 expression. As discussed in the Actions mailed on 8/14/24 and 5/9/25, the question is whether an ordinary skilled artisan would be motivated with a reasonable expectation of success to treat pruritus/itch as a symptom of AD. The Examiner maintains that the answer to this question is yes in light of the teachings of Lee et al. More specifically, Lee et al. demonstrates a cascade pathway that is disrupted when LEKTI is dysfunctional; more specifically, when the LEKTI protein is dysfunctional, its inhibitory effect on KLK5, 7 and 14 is reduced and/or eliminated thereby allowing KLK5, 7, and 14 to activate PAR-2, which is known to induce pruritus/itch in AD patients, and which is known to synergistically interact with TRPV1 to amplify pruritus/itch in AD patients. Therefore, contrary to Applicant’s argument, an ordinary skilled artisan would be motivated to ameliorate pruritus or itch as a symptom of AD by administering onto the skin of a mammal suffering from AD a microbe encoding LEKTI protein domain 6 encoded by a SPINK5 gene given that LEKTI protein domain 6 would indirectly inhibit PAR-2 activation and preclude PAR-2 from interacting with TRPV1 via KLK5 and 7 inhibition thereby treating pruritus/itch in AD mammals.
Although Lee demonstrates that a LEKTI protein domain 6 is an indirect TRP channel antagonist via KLK5/7 and PAR-2 inhibition, it is unnecessary for a prior art reference to teach and/or suggest the newly added functional limitation. As stated in the rejection supra, since the cited art teaches the claimed manipulative step by administering the identical claimed product, the function of the known product does not per se render a claimed invention patentable because the function is necessarily present. MPEP 2145(II) states that the “[m]ere recognition of latent properties in the prior art does not render nonobvious an otherwise known invention.” In re Baxter Travenol Labs., 952 F.2d 388 (Fed. Cir. 1991). "The fact that appellant 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." Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985). Moreover, pursuant to MPEP 2112.01(II), “[p]roducts of identical chemical composition cannot have mutually exclusive properties.” In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990). A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical chemical structure, the properties applicant discloses and/or claims are necessarily present. Id. (Applicant argued that the claimed composition was a pressure sensitive adhesive containing a tacky polymer while the product of the reference was hard and abrasion resistant. “The Board correctly found that the virtual identity of monomers and procedures sufficed to support a prima facie case of unpatentability of Spada’s polymer latexes for lack of novelty.”). Accordingly, contrary to Applicant’s argument, even if the cited references did not teach that the LEKTI protein domain 6 indirectly inhibited TRP channel activity, such lack of teaching would not preclude a finding of obviousness because the cite references teach and/or suggest the structural limitations of the claimed microbe genetically modified to express a LEKTI protein domain 6. Thus, the microbe genetically modified to express a LEKTI protein domain 6 would necessarily exhibit the functional property of the claimed microbe genetically modified to express a LEKTI protein domain 6.
In response to Applicant’s argument that the presently claimed invention is based, at least in part, on the surprising finding that topically administering the claimed microbe to the skin of a subject can be used to decrease one or more symptoms of pruritus as exemplified in Example 9 in the specification (See Response received on 9/9/25, pg. 9-10), it is found unpersuasive. Pursuant to MPEP 716.02(c)(II), expected beneficial results are evidence of obviousness of a claimed invention, just as unexpected results are evidence of unobviousness thereof." In re Gershon, 372 F.2d 535, 538, 152 USPQ 602, 604 (CCPA 1967). As discussed supra, the combined teachings of Whitfill and Lee suggest that a LEKTI protein domain 6 exhibits an antagonistic function in a downstream cascade pathway by directly inhibiting KLK5 and 7 expression, which in turn indirectly inhibits PAR-2 activation and precludes PAR-2 from synergistically interacting with TRPV1. Thus, the inhibitory effect exhibited by the LEKTI protein domain 6 in instant Example 9 would be expected.
Notwithstanding the cited references’ teachings, it is noted that the data provided in Example 9 does not clearly indicate that the inhibitory effect on TRPV1 or 4 is solely dependent upon the presence of the LEKTI protein domain 6. More specifically, in [0478] and [0480], it is stated that “[a]ntagonist treatment was combined with LEKTI D6 treatment” (emphasis added). As such, it would appear that the LEKTI D6 treatment was in combination with either capsazepine for TRPV1 or Ruthenium Red for TRPV4 as known antagonists (See instant, [0474], [0478], [0480]). If the LEKTI D6 treatments was combined, meaning both agents combined in culture together, then it is not readily apparent that the inhibitory effect identified is due solely to the LEKTI D6 component and not attributed to the known antagonistic agent. Figures 7B and 8B appear to depict the inhibitory effect of the known antagonists alone. It is respectfully requested for Applicants to clarify whether the data depicted in the tables in [0478] and [0480] are for combined treatments or LEKTI D6 alone, in particular, in a Declaration/Affidavit.
Accordingly, Applicants’ arguments as they pertain to the new 103(a) rejection supra are found unpersuasive.
Conclusion
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654