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Any rejection or objection from the previous office action, which is not restated here, is withdrawn.
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. The amendment received on June 17, 2026, amended claims 63-64 and 67.
Claims 1, 9, 56-58, 60-61, and 63-67 are currently pending and claims 1, 56, 60-61, and 63-67 are under consideration as claims 57-58 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention and claim 9 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim.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.
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 6/17/26, with respect to the claim objection have been fully considered and are persuasive. The objection of claims 63-64 has been withdrawn.
Applicant’s arguments, see Response, filed 6/17/26, with respect to the 112(a), new matter, rejection have been fully considered and are persuasive. The rejection of claim 67 as failing to comply with the written description requirement has been withdrawn.
Maintained Rejections
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 63-67 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 between 15% and 83.8% 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 between 15% and 83.8% 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 between 15% and 83.8% 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 between 15% and 83.8% 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 filed 6/17/26 for claims 1, 56, 60-61, and 63-67 have been fully considered but they are not persuasive for the following reasons.
In response to Applicant’s argument, i.e., the Whitfill reference is not available as prior art against the pending claims under the 35 USC 102(b)(2)(c) exception (See Applicant’s Response received on 6/17/26, pg. 6-7), it is found unpersuasive. MPEP 2152, AIA 35 U.S.C. 102(a) provides that: [a] person shall be entitled to a patent unless—
(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention (emphasis added); or
(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
As indicated in the 103 rejection heading, the publication date of the Whitfill reference is 2/7/19, and as indicated in the “Priority” section, the effective filing date of the instant application is 11/4/26. As such, pursuant to MPEP 2152, the Whitfill reference constitutes prior art as a 102(a)(1) and/or 102(a)(2) reference since its publication date is prior to the instant effective filing date. It is acknowledged that the Whitfill reference would be disqualified as prior art under the 102(b)(2)(C) exception in light of common ownership. However, such exception does not apply for prior art that is considered 102(a)(1) art.
MPEP 2153 discusses the exceptions to 102(a)(1). There are two exceptions to disqualify prior art that would otherwise qualify as prior art under AIA 35 USC 102(a)(1) except that it was publicly available within one year or less before the effective filing date of the instant application. Exception 102(b)(1)(A) applies when: (1) one year or less before the effective filing date of the claimed invention; and (2) by the inventor or a joint inventor or by another who obtained the subject matter disclosed directly or indirectly from the inventor or a joint inventor (i.e., an inventor-originated disclosure) (See MPEP 2153). As discussed in the rejection heading, the inventors of the instant application and the Whitfill reference are distinct. As such, the 102(b)(1)(A) exception is not applicable. Exception 102(b)(1)(B) applies when: (1) one year or less before the effective filing date of the claimed invention; and (2) the subject matter disclosed had been previously publicly disclosed by the inventor, a joint inventor, or another who obtained the subject matter directly or indirectly from the inventor or joint inventor, i.e., grace period intervening disclosure by third party that was directly or indirectly obtained from the inventor or joint inventor. Since there is no indication that a third party obtained the subject matter directly or indirectly from an inventor of the instant application, the 102(b)(1)(B) exception is not applicable. Therefore, the Whitfill reference constitutes prior art as a 102(a)(1) reference. Thus, contrary to Applicant’s argument, the Whitfill reference is available as prior art as a 102(a)(1) reference.
Accordingly, Applicants’ arguments are found unpersuasive.
Conclusion
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/THEA D' AMBROSIO/Primary Examiner, Art Unit 1654
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