DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Status
Applicant’s preliminary amendment filed March 12, 2024 has been received and entered.
Claims 4-10, 12, 15-17, and 19-22 have been amended.
Claims 11 and 23-30 have been canceled.
Claims 1-10 and 12-22 are pending and under consideration.
Priority
This application is a 371 of PCT/US2022/076387 filed September 14, 2022, which claims the benefit of U.S. Provisional Application No. 63/244,427 filed September 15, 2021.
Information Disclosure Statement
The information disclosure statement (IDSs) submitted on 3/12/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Claim Objections
Claims 1, 3, 10, 16, and 20 are objected to because of the following informalities:
Claim 1 (line 3) - there is an extra space between “therapeutically” and “effective”.
Claim 3 recites “a HCDR1, a HCDR2, and a HCDR3”and “a LCDR1, a LCDR2, and a LCDR3”, however, should read “an HCDR1, an HCDR2, and an HCDR3” and “an LCDR1, an LCDR2, and an LCDR3”.
Claim 10 (line 1) - should recite, “wherein the patient is treated with the anti-IL-13 antibody…”.
Claim 16 is contains awkward phrasing. It is suggested that the claim be amended to read, “…further comprising assessing the patient before and after treatment for one or more of the following: IGA PN-S, IGA PN-A, Skin Pain NRS, nighttime awakenings DSS, PGI-S-PN, DLQI, PAS, PROMIS anxiety and Depressive Symptoms, and EuroQol-5D (EQ-5D-5L)”.
Claim 16 recites several acronyms (IGA PN-S, IGA PN-A, NRS, DSS, PGI-S-PN, DLQI, PAS, PROMIS and EuroQol-5D (EQ-5D-5L) which should be defined upon first occurrence.
Claim 20 (line 2) - refers to PN, however, the abbreviation is not set forth in claim 1. For consistency, Applicant should amend the claim to read prurigo nodularis. Alternatively, Applicant may amend claim 1 to add the abbreviation PN. If the latter is selected, the PN abbreviation should be used in the remainder in claims in lieu of the term “prurigo nodularis”.
Claim 20 (line 3) - should read “an IGA PN-S score”.
Appropriate correction is required.
Claim Rejections - 35 USC § 112(b)
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
Claims 10 and 20-21 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 10 recites the patient is further treated with a loading dose of 500 mg of the anti-IL-13 antibody at week 0 (baseline) and week 2. However, the claim depends from claim 9 which recites that the patient is administered a dose of 250 mg once every two weeks. It does not make sense that the patient is further treated with a loading dose, when the loading doses are the first doses administered to the patient. It is recommended that the claim be amended to read, “the patient is treated with a loading dose…”, instead of “further treated”.
Claim 20 recites “…wherein the patient has (1) a clinical diagnosis of PN for at least 6 months; (2) PN lesions on upper limbs, trunk, and/or lower limbs, at least 20 nodules on the entire body with a bilateral distribution…”. However, while the claim stipulates that the patient must have at least 20 lesions on the entire body, it is unclear the number of lesions on the upper or lower limbs a patient would need to have to be diagnosed as having moderate to severe prurigo nodularis.
Claim 20, steps 3-4 are drawn to baseline scores. However, there is no antecedent basis for the term “at baseline” in any of the claims from which claim 20 ultimately depends.
Claim 21 recites “…wherein the patient has inadequate response to topical corticosteroids or topical calcineurin inhibitors, or topical corticosteroids or topical calcineurin inhibitors are medically inadvisable for the patient”. The claim is confusing as written. It is suggested the claim be amended to recite “…wherein the patient has inadequate response to topical corticosteroids or topical calcineurin inhibitors, or wherein topical corticosteroids or topical calcineurin inhibitors are medically inadvisable for the patient”
Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
WRITTEN DESCRIPTION
Claims 1-2, 7-10, and 12-22 are rejected under 35 U.S.C. 112(a), 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, at the time the application was filed, had possession of the claimed invention.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the claimed genus. See MPEP § 2163.
Claim 1 is drawn to of treating prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-13 inhibitor.
Claim 2 limits the IL-13 inhibitor to an anti-IL-13 antibody.
The claims encompass a large genus of structurally distinct molecules that block IL-13.
The specification discloses that in some embodiments the IL-13 inhibitor is an anti-IL-13 antibody. Other IL-13 inhibitors include small molecule inhibitors, antisense oligonucleotides, RNAi agents, aptamers, or peptides that interact with IL-13 or its receptors and decreases or eliminates one or more activities or functions associated with IL-13 [0014].
The instant specification only describes one anti-IL-13 antibody (i.e., lebrikizumab). However, only a clinical trial plan for evaluating the effectiveness and safety of lebrikizumab is described in the examples [pg. 17-25]. There is no description that the therapeutic treatment of PN with any IL-13 inhibitor was actually performed and its pharmacological effect was confirmed. The detailed description of the invention merely infers that an IL-13 inhibitor such as lebrikizumab may be beneficial to the patient based on an observed increase in IL-13 levels in PN patient samples.
The state of the art regarding IL-13 inhibitors is complex, and although they share the broad goal of reducing type 2 inflammation, they differ significantly in what targets they bind and their mechanism of action. For example, Okragly et al. (Dermatol Ther (Heidelb), 2023; 13(7):1535–1547) teaches lebrikizumab is a potent, neutralizing high-affinity antibody binds directly to soluble IL-13 (at helices B and C) to prevent the formation of the signaling receptor heterodimer, without blocking natural clearance via the decoy receptor IL-13Ra2, while tralokinumab and cendakimab are monoclonal antibodies IL-13 that prevent its binding to IL-13Ra1 [Abstract].
However, Applicant has only described a single IL-13 inhibitor, lebrikizumab. Therefore, the properties of one IL-13 inhibitor cannot be applied to other IL-13 inhibitors, as the properties of the claimed il-13 inhibitors are not predictive of the full genus of inhibitors.
The instant application has not provided a sufficient description showing possession of the necessary functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the applicant was in possession of the genus of IL-13 inhibitors encompassing various structures, specificities and functions. Further, the Court has interpreted 35 U.S.C. § 112, first paragraph, to require the patent specification to “describe the claimed invention so that one skilled in the art can recognize what is claimed. Enzo Biochem, Inc. v. Gen-Probe, Inc., 63 USPQ2d 1609 and 1618 (Fed. Cir. 2002). In evaluating whether a patentee has fulfilled this requirement, our standard is that the patent’s “disclosure must allow one skilled in the art ‘to visualize or recognize the identity of’ the subject matter purportedly described.” Id. (quoting Regents of Univ. of Cal. v. Eli Lilly & Co., 48 USPQ2d 1398 (Fed Cir. 1997)).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with
reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession
of the invention. The invention is, for purposes of the 'written description’ inquiry, whatever is now
claimed." (See Vas-Cath, p. 1117). The specification does not "clearly allow persons of ordinary skill in
the art to recognize that [he or she] invented what is claimed." (See Vas-Cath, p. 1116). Also, it is noted that the Court has held that the disclosure of screening assays and general classes of compounds was not adequate to describe compounds having the desired activity: without disclosure of which peptides, polynucleotides, or small organic molecules have the desired characteristic, the claims failed to meet the description requirement of § 112. See University of Rochester v. G.D. Searle & Co., Inc., 69 USPQ2d 1886,1895 (Fed. Cir. 2004).
Meeting the written description threshold requires showing that the applicant was in “possession” of the claimed invention at the time of filing. Vas-Cath, 935 F.2d at 1563-1564. Support
need not describe the claimed subject matter in exactly the same terms as used in the claims. Eiselstein
v. Frank, 52 F.3d 1035, 1038 (Fed. Cir. 1995). This support cannot be based on obviousness reasoning —
i.e., what the written description and knowledge in the art would lead one to speculate as to modifications the inventor might have envisioned, but failed to disclose. Lockwood v. American Airlines, Inc., 107 F.3d 1565, 1572 (Fed. Cir. 1997). Ariad points out, the written description requirement also
ensures that when a patent claims a genus by function, the specification recites sufficient materials to
accomplish that function - a problem that is particularly acute in biological arts." Ariad, 598 F.3d at 1352-3.
Given the claimed broadly class of IL-13 inhibitors, in the absence of sufficient disclosure of relevant identifying characteristics, the patentee must establish “a reasonable structure-function correlation” either within the specification or by reference to the knowledge of one skilled in the art with functional claims. There is insufficient written description of the required kind of structure- identifying information about the corresponding makeup of the claimed SGLT-2 inhibitors to demonstrate possession. Also, see Amgen Inc. v. Sanofi, Aventisub LLC, No. 2017-1480 (Fed. Cir. 2017). Thus, one of skill in the art would conclude that the specification fails to provide adequate written description to demonstrate that Applicant was in possession of the claimed genus. See Eli Lilly, 119 F. 3d 1559, 43, USPQ2d 1398.
Claims 7-10 and 12-22 are included in the rejection because they depend from a rejected claim and fail to resolve the issue.
ENABLEMENT
Claims 1-10 and 12-22 are rejected under 35 U.S.C. 112(a), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
As a general rule, enablement must be commensurate with the scope of claim language. MPEP § 2164.08 states, “The Federal Circuit has repeatedly held that “the specification must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation.” In re Wright, 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993)” (emphasis added). The “make and use the full scope of the invention without undue experimentation” language was repeated in 2005 in Warner-Lambert Co. v. Teva Pharmaceuticals USA Inc., 75 USPQ2d 1865, and Scripps Research Institute v. Nemerson, 78 USPQ2d 1019 asserts: “A lack of enablement for the full scope of a claim, however, is a legitimate rejection.” The principle was explicitly affirmed in Auto. Tech. Int’l, Inc. v. BMW of N. Am., Inc., 501 F.3d 1274, 84 USPQ2d 1108 (Fed. Cir. 2007), Monsanto Co. v. Syngenta Seeds, Inc., 503 F.3d 1352, 84 U.S.P.Q.2d 1705 (Fed. Cir. 2007), and Sitrick v. Dreamworks, LLC, 516 F.3d 993, 85 USPQ2d 1826 (Fed. Cir. 2008). See also In re Cortright, 49 USPQ2d 1464, 1466 and Bristol-Myers Squibb Co. v. Rhone-Poulenc Rorer Inc., 49 USPQ2d 1370.
The factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 8 USPQ2d 1400 (Fed. Cir. 1988). Among these factors are: (1) the nature or the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary. When the above factors are weighed, it is the examiner’s position that one skilled in the art could not practice the invention without undue experimentation. Some experimentation is not fatal; the issue is whether the amount of experimentation is “undue”; see In re Vaeck, 20 USPQ2d 1438, 1444.
The nature of the invention and (5) The breadth of the claims:
Claim 1 is drawn to a method of treating prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-1 3 inhibitor.
Claims 2-6 are drawn to the anti-IL-13 antibody lebrikizumab.
Kowalski et al. (Clin Cosmet Investig Dermatol, 2019;12:163–172) teaches prurigo nodularis (PN) is a complex chronic condition with highly pruritic, hyperkeratotic papules or nodules arising in the setting of chronic pruritus. While PN may serve as a phenotypic presentation of several underlying conditions such as atopic dermatitis, chronic kidney disease-related pruritus, and neurological diseases, it represents a distinct clinical entity that may persist despite the removal of the underlying cause, if one is identified. Neuronal proliferation, eosinophils, mast cells, and small-fiber neuropathy play a role in the production of pruritus in PN, although the exact mechanism has not yet been established [Abstract]. The initiation of an itch-scratch cycle perpetuates the development of PN and explains the propensity for symmetrical distribution of lesions and the characteristic absence on the upper mid back. Lesions can number from several to hundreds, and can vary greatly in size [Introduction, par. 1]. Recent work on the pathogenesis of PN has pointed to a complex interplay of pro-inflammatory and pruritogenic substances in addition to increased local concentrations of neuropeptides in lesional skin that may be responsible for the alterations in nerve density and cutaneous inflammation found in PN [Introduction, par. 2].
Regarding pruritus specifically, Kowalski et al. teaches it is a symptom present in many diseases, and a certain subset of patients may be predisposed to a higher sensitivity or lower tolerance to pruritus, developing a clinical prurigo response under the influence of the itch-scratch cycle. Resolution of the underlying etiology with eventual neuronal sensitization can ensue leading to perpetuation and spread of this secondary response. Chronic scratching alters the environment in the dermis and epidermis as evidenced by increased levels of neuropeptides and neurohyperplasia [Introduction, par. 2].
(2) The state of the prior art and (4) The predictability or unpredictability of the art:
The state of the art with regard to treating prurigo nodularis or reducing pruritus associated with prurigo nodularis is complex. For example, Kowalski et al. teaches treatment of PN typically relies on the use of topical or intralesional steroids, though more severe or recalcitrant cases often necessitate the use of phototherapy or systemic immunosuppressives. Thalidomide and lenalidomide can both be used in severe cases; however, their toxicity profile makes them less favorable. Opioid receptor antagonists and neurokinin-1 receptor antagonists represent two novel families of therapeutic agents which may effectively treat PN with a lower toxicity profile than thalidomide or lenalidomide [Abstract].
Given the lack of predictability in the treatment of prurigo nodularis, the skilled artisan would have to engage in undue experimentation to first identify individuals to which the instant method would apply followed by selection of the appropriate IL-13 inhibitor.
6) the amount of direction or guidance provided by the inventor; 7) the existence of working examples;
The instant claims are directed to a treatment for prurigo nodularis (PN) or reducing pruritus associated with PN, comprising administering an IL-13 inhibitor. However, the instant specification sets forth no examples treating prurigo nodularis or reducing pruritus with any IL-13 inhibitor. The instant specification only describes one anti-IL-13 antibody (i.e., lebrikizumab). Furthermore, only a clinical trial plan for evaluating the effectiveness and safety of lebrikizumab is described in the examples [pg. 17-25]. There is no description that the therapeutic treatment of PN with any IL-13 inhibitor was actually performed and its pharmacological effect was confirmed. The detailed description of the invention merely infers that an IL-13 inhibitor such as lebrikizumab may be beneficial to the patient based on an observed increase in IL-13 levels in PN patient samples.
As such, it would be hard to envision what IL-13 inhibitor would be effective in the treatment of prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient as broadly claimed. One of skill in the art would be required to engage in extensive, difficult experimentation to first identify what IL-13 inhibitor to which the method can apply which is known to be unpredictable as indicated above. This required experimentation is undue.
In conclusion, the claimed invention does not provide enablement for treatment of prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-1 3 inhibitor. Thus for the reasons outlined above, the specification is not considered to be enabling for one skilled in the art to make and use the claimed invention as the amount of experimentation required is undue, due to the broad scope of the claims, the lack of guidance and working examples provided in the specification. Therefore, the specification is not representative of the instant claims and the specification is not fully enabled for the instant claims. In view of the above, one of skill in the art would be forced into undue experimentation to practice the claimed invention.
Claims 7-10 and 12-22 are included in the rejection as they depend from or otherwise require all the limitations of a rejected claim and fail to resolve the issues.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-6, 15-16, and 19-21 are rejected under 35 U.S.C. 103 as being unpatentable over Müller et al. (Expert Opin Biol Ther, 2022; 22(1):47-58; cited IDS 3/12/2024) (“Müller”).
The instant claims are drawn to a method of treating prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-13 inhibitor, wherein the IL-13 inhibitor is an anti-IL-13 antibody, comprising a VH and a VL, comprising SEQ ID NO: 7 and SEQ ID NO: 8, respectively, wherein the VH comprises an HCDR1 comprising SEQ ID NO: 1, an HCDR2 comprising SEQ ID NO: 2, and an HCDR3 comprising SEQ ID NO: 3, and the VL comprises an LCDR1 comprising SEQ ID NO: 4, an LCDR2 comprising SEQ ID NO: 5, and an LCDR3 comprising SEQ ID NO: 6, wherein the antibody is lebrikizumab. Further comprising determining the Itch Numerical Rating Scale (NRS) score of the patient before and after the treatment and the Investigator's Global Assessment (IGA) of prurigo nodularis stage before and after treatment, wherein the patient has moderate to severe prurigo nodularis for at least 6 months or has lesions on upper limbs, trunk, and/or lower limbs, at least 20 nodules on the entire body with a bilateral distribution, and an inadequate response to topical corticosteroids.
Müller teaches anti-IL-13 antibodies tralokinumab and lebrikizumab as possible therapeutics for prurigo nodularis (PN) [pg. 8, Expert Opinion] (instant claims 1-6). Müller teaches PN, the most common subtype of chronic prurigo, is a multidisciplinary clinical condition characterized by chronic pruritus (pruritus lasting ≥ 6 weeks) and prolonged scratch behavior that leads to multiple localized or symmetrically distributed generalized hyperkeratotic, crusted, and excoriated nodular lesions. Predominantly easily accessible parts of the body are affected by few to hundreds pruritic nodules ranging from millimeters to 3 cm in diameter (e.g. shoulders, upper and lower limbs, buttocks, and back [Introduction, par. 1] (instant claims 19-20). The diagnosis of PN is usually made clinically as part of a detailed patient-individual work-up involving history taking and a close physical examination of the entire skin. Validated measurement instruments help to assess and monitor patient-reported outcomes such as pruritus intensity (e.g. numeric and verbal rating scale) and visual analogue scale for pruritus) and other pruritus associated burden on the patient (e.g. health-related quality of life measured by the Dermatology Life Quality Index or ItchyQol) before and after treatment start [pg. 1, last par. - pg. 2, par. 1] (instant claims 15-16).
Therapies of PN primarily aim at breaking the vicious itch-scratch cycle and healing pruritic skin lesions due to the reduction of pruritus. However, the vicious itch-scratch cycle is difficult to treat with available therapies and patients are often recalcitrant to current therapies. The international guidelines recommend a laddered approach beginning with topical treatment. Topical treatment options consist of emollients, topical (medium to high-potency) or intralesional corticosteroids, calcineurin inhibitors, and capsaicin. Final treatment options include the use of biologics, such as monoclonal antibodies [pg. 3, col. 2] (instant claim 21).
Müller teaches that current available monoclonal antibodies target predominantly Th2 pathways in which receptors for IL-4, IL-13, and IL-31 play an important role. Specifically, IL-4 and IL-13 are capable of inducing chronic pruritus by binding to IL-4Ra which immediately activates sensory neurons that take part in aberrant neuroimmune interactions driving the vicious itch-scratch cycle, with IL-13 directly activating sensorial neurons [pg. 3, col. 1, par. 4-5].
Recent studies report the antipruritic effects of dupilumab and the anti-IL 13 monoclonal antibodies tralokinumab and lebrikizumab, currently clinically tested in atopic dermatitis, that all disrupt type II immune signaling. Dupilumab is an anti-IL-4/IL-13 monoclonal antibody that interferes with Th2 cell differentiation, alternative macrophage activation as well as IgE production by B cells [pg. 4, par. 1-3]. Müller discloses several studies illustrate dupilumab’s beneficial effects to both flattening of nodular skin lesions and pruritus amelioration in pediatric PN and PN in the elderly which was refractory to multimodal previous therapies. In the vast majority of patients, pruritus improved from 8.6 ± 1.9 to 1.8 ± 2.3 points on the numeric rating scale (range 0-10) prior to and after starting dupilumab. Although it is possible that the effectiveness of dupilumab in treating PN is a result from an atopic background in PN patients, comparing PN patients with and without atopic predisposition, no differences regarding overall therapy response or pruritus amelioration was found [pg. 4, col. 2].
Müller teaches anti-IL-13 antibodies tralokinumab and lebrikizumab. IL-13 is a Th2 cell-derived cytokine that plays an important role in itch signaling, skin barrier disruption, and inflammation. Tralokinumab specifically neutralizes IL-13 by the inhibition of binding to both IL-13Ra1 and IL-13Ra, and was found to be effective in clinical trials aimed at reducing pruritus early in adults suffering from moderate to-severe atopic dermatitis. As tralokinumab also prevents the binding of IL-13 to IL-13Ra2, pruritus reducing mechanisms might be similar to dupilumab as the receptor has been discovered to reduce IL-4 signaling. IL-13 is one of the triggers that upregulates the expression of periostin, a central itch inducing extracellular matrix protein secreted by epithelial and endothelial cells as well as by fibroblasts. As such, the inhibition of IL-13 and consequently periostin might be a crucial approach in the future therapy of PN [pg. 6, Section 4.1.1.1.2].
Regarding lebrikizumab, Müller teaches it is a monoclonal antibody that prevents the formation of the IL-13Ra1/IL-4Ra heterodimer receptor signaling complex, but does not block the binding of IL-13 to the IL-13Ra2 receptor. Similar to tralokinumab, lebrikizumab achieved a rapid pruritus reduction and was generally well-tolerated in adults with moderate to severe atopic dermatitis in several clinical trials [pg. 6, Section 4.1.1.1.3].
Müller concludes, tralokinumab and lebrikizumab (both blocking IL-13), have the potential to be successfully used in treating PN [pg. 8, Expert Opinion].
The instant specification discloses the amino acid sequences for lebrikizumab heavy and light chain variable regions, including their respective CDR regions, in Table 1 [0018], which correspond to the amino acid sequences (SEQ ID NOs) recited in instant claims 3-5.
The teachings of Müller differ from the present invention in that although the anti-IL-13 antibody lebrikizumab is offered as a potential therapeutic for the treatment of prurigo nodularis, mainly by reducing the severe itch (i.e., pruritus), it does not specifically demonstrate the pharmacological efficacy of lebrikizumab in treating PN. One of ordinary skill in the art would have a reasonable expectation of success in treating prurigo nodularis with lebrikizumab given that Müller teaches lebrikizumab rapidly reduces pruritus in adults with moderate to severe atopic dermatitis similar to the anti-IL-4/IL-13 antibody dupilumab, which is also effective in treating prurigo nodularis refractory to previous therapies in patients without atopic dermatitis. Therefore, pruritus control leads to healing of skin lesions and decrease of pruritic nodules. The skilled artisan would be motivated to treat prurigo nodularis with an anti-IL-13 antibody such as lebrikizumab because of the limited treatment options and the severity of the condition, which is associated with the highest pruritus intensities with prolonged scratch behavior that leads to the formation of nodules that can be immensely disfiguring, and highest burden of disease compared to other pruritic entities. Affected patients suffer from a significant impairment of health-related quality of life, social interaction, sleep, and mental health [pg. 8, Expert Opinion, par. 1].
KSR International Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741 (2007), discloses that if a technique has been used to improve one method, and a person of ordinary skill would recognize that it would be used in similar methods in the same way, using the technique is obvious unless its application is beyond that person’s skill. It would be obvious to apply a known technique to a known product to be used in a known method that is ready for improvement to yield predictable results. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention.
Claims 7-10, 17-18, and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Müller et al. (Expert Opin Biol Ther, 2022; 22(1):47-58; cited IDS 3/12/2024) (“Müller”) as applied to claims 1-6, 15-16, and 19-21, and in further view of Guttman-Yassky et al. (JAMA Dermatol, 2020; 156(4):411–420; cited IDS 3/12/2024) (“Guttman”).
The instant claims are drawn to a method of treating prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-13 inhibitor, wherein the IL-13 inhibitor is the anti-IL-13 antibody lebrikizumab. The antibody is administered subcutaneously to the patient at a dose of 250 mg to 500 mg, wherein the anti- IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every two weeks, wherein the patient is treated with a loading dose of 500 mg of the anti-IL-13 antibody at week 0 (baseline) and week 2, wherein the antibody is administered in a prefilled syringe to a patient aged 18 or older.
The teachings of Müller are set forth above. In addition Müller teaches that the dosage of dupilumab administered for the treatment of prurigo nodularis was adapted to the recommended dosage in atopic dermatitis [pg. 4, col. 1, par. 2].
Müller does not teach a dosing regimen for lebrikizumab.
Guttman teaches a Phase 2b randomized clinical trial evaluating the safety and efficacy of lebrikizumab in adults with moderate to severe atopic dermatitis. Patients were randomized and administered subcutaneous injections of lebrikizumab [Interventions, pg. 1] (instant claim 7). Patients in Treatment Group 3 were administered 250 mg lebrikizumab every 2 weeks up to week 14 and were administered a loading dose of 500 mg at baseline and week 2 (instant claims 8-10). Males and Females 18 years or older were included in the study [Key Inclusion Criteria, Supp. 2, pg. 11] (instant claim 22).
Guttman further teaches that lebrikizumab 125 mg/mL injectable is delivered in a pre-filled syringe (PFS) [Supp. 2, pg. 10] (instant claims 17-18).
Müller teaches that it would be obvious to treat prurigo nodularis and the associated severe pruritus with lebrikizumab based on its efficacy in treating atopic dermatitis, however, does not teach any dosing information. Given that Müller teaches that the antibody dupilumab was effectively administered to patients with PN using the same dosing regimen used in treating atopic dermatitis, the skilled artisan would have more than a reasonable expectation of success in adopting the lebrikizumab dosing regimen used for treating moderate to severe atopic dermatitis as taught by Guttman, as this regimen was found both safe and effective in ameliorating pruritus in this patient population. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Claims 12-14 are rejected under 35 U.S.C. 103 as being unpatentable over Müller et al. (Expert Opin Biol Ther, 2022; 22(1):47-58; cited IDS 3/12/2024) (“Müller”), in further view of Guttman-Yassky et al. (JAMA Dermatol, 2020; 156(4):411–420; cited IDS 3/12/2024) (“Guttman”), as applied to claims 1-10 and 15-22 above, and in further view of FDA Multi-Disciplinary Review and Evaluation of EBGYLSS (lebrikizumab) (www.fda.gov/media/193748/download, Version October 12, 2018) (“FDA Review”).
The instant claims are drawn to a method of treating prurigo nodularis or reducing pruritus associated with prurigo nodularis in a patient in need thereof, the method comprising administering to the patient a therapeutically effective amount of an IL-13 inhibitor, wherein the IL-13 inhibitor is the anti-IL-13 antibody lebrikizumab. The antibody is administered subcutaneously to the patient at a dose of 250 mg to 500 mg, wherein the anti- IL-13 antibody is administered subcutaneously to the patient at a dose of 250 mg once every two weeks, wherein the patient is treated with a loading dose of 500 mg of the anti-IL-13 antibody at week 0 (baseline) and week 2, wherein the antibody is administered in a prefilled syringe to a patient aged 18 or older. The antibody is administered for a period of 16 to 24 weeks.
The teachings of Müller and Guttman are set forth above.
Müller does not teach a dosing regimen for lebrikizumab. Guttman teaches lebrikizumab is administered every two weeks, with the last dose administered at week 14. Guttman does not teach dosing for 16 to 24 weeks.
The FDA Review teaches the recommended dosage of lebrikizumab is an initial dose of 500 mg at Week 0 and Week 2, followed by 250 mg every two weeks until Week 16 or later, when adequate clinical response is achieved. [Section 1.1 Product Introduction] (instant claims 12-14).
Although the studies taught by Guttman administered lebrikizumab up to week 14, it would be obvious to one of ordinary skill in the art that it could be administered for a longer duration, including 16 weeks or more, until symptoms improve as evidenced by the FDA notice. Given the safety of administering lebrikizumab, one would have more than a reasonable expectation of success in continuing treatment for 16 or 24 weeks, or longer. Therefore, the instant invention was prima facie obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention in view of the combined references.
Double Patenting
Pursuant to 37 CFR 1.78(f), when two or more applications filed by the same applicant or assignee contain patentably indistinct claims, elimination of such claims from all but one application may be required in the absence of good and sufficient reason for their retention during pendency in more than one application. Applicant is required to either cancel the patentably indistinct claims from all but one application or maintain a clear line of demarcation between the applications. See MPEP § 822.
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1-10 and 12-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 7-8, 15, 17-18, 20, and 37-42 of U.S. Application No. 18/682,575 in view of Müller et al. (Expert Opin Biol Ther, 2022; 22(1):47-58; cited IDS 3/12/2024) (“Müller”).
Copending claims 1, 3, and 7-8 are drawn to a method for treating moderate to severe atopic dermatitis in a patient comprising administering an anti-IL-13 antibody reciting the SEQ ID NOs corresponding to the CDRs of the anti-IL-13 antibody lebrikizumab, administered 250 mg every two weeks with a loading dose of 500 mg administered at baseline and week 2. Copending claim 15 recites the patient is 12 or older. Copending claims 15-17 and 20 are drawn to evaluation and scoring of patient symptoms. Copending claims 37-39 are drawn to lebrikizumab and its VH and VL amino acid sequences. Copending claims 40-42 are directed towards methods of administration with a prefilled syringe.
The amino acid sequences and the corresponding SEQ ID NOs of the anti-IL-13 antibody (lebrikizumab) recited in the copending claims are 100% identical to the amino acid sequences recited in the instant claims.
The claims of the copending application are drawn to the administration of an anti-IL-13 antibody (lebrikizumab) for the treatment of moderate to severe atopic dermatitis. However, the copending application does not disclose the antibody is administered as treatment for prurigo nodularis (PN) or reducing pruritus associated with PN.
However, Müller teaches anti-IL-13 antibodies such as tralokinumab and lebrikizumab as possible therapeutics for prurigo nodularis (PN) [pg. 8, Expert Opinion] based on the effectiveness of both antibodies in achieving rapid pruritus reduction in adults with moderate to severe atopic dermatitis [pg. 6, Section 4.1.1.1.3] in combination with the success of the off-label use of dupilumab in treating PN. Dupilumab is an anti-IL-4/IL-13 antibody used for treating moderate to severe atopic dermatitis. When dupilumab was administered to patients with PN without any atopic dermatitis history, including patients administered prior therapies (e.g., corticosteroids), the PN was resolved [pg. 4, col. 2].
Therefore, it would have been obvious to one of ordinary skill in the art that the treatment method disclosed by the copending application could be applied to patients with prurigo nodularis as evidenced by Müller that teaches the identical IL-13 inhibitor (lebrikizumab) as a promising treatment for prurigo nodularis. One would have a reasonable expectation of success in administering to a patient the dosing regimen of lebrikizumab recited in the copending application as evidenced by Müller that teaches the dupilumab dosing regimen used for treating atopic dermatitis was successfully adopted in treating PN [pg. 4, col. 1, par. 2]. Therefore, the combination of prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Claims 1-10 and 12-22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 8, 11, 13, 15, 18, 22-28, and 56 of U.S. Application No. 18/862,867 in view of Müller et al. (Expert Opin Biol Ther, 2022; 22(1):47-58; cited IDS 3/12/2024) (“Müller”).
Copending claims 1-4 are drawn to methods of treating moderate to severe atopic dermatitis to a patient comprising administering lebrikizumab. Copending claim 5 recites the treatment period. Copending claims 8 and 11 are drawn to the lebrikizumab dosing schedule, including loading doses. Copending claim 13 recites the age range of the patient. Copending claim 15 recites the patient had inadequate response to corticosteroids. Copending claim 18 recites subcutaneous lebrikizumab administration. Copending claims 22-26 are drawn to assessing the patient response using one or more scoring assessments. Copending claims 27-28 are drawn to a prefilled syringe. Copending claim 56 recites a pharmaceutical composition comprising lebrikizumab.
The claims of the copending application are drawn to the administration of lebrikizumab for the treatment of moderate to severe atopic dermatitis. However, the copending application does not disclose the antibody is administered as treatment for prurigo nodularis (PN) or reducing pruritus associated with PN. The copending claims do not specifically recite the treatment is for ages 18 and over.
However, Müller teaches anti-IL-13 antibodies such as tralokinumab and lebrikizumab as possible therapeutics for prurigo nodularis (PN) [pg. 8, Expert Opinion] based on the effectiveness of both antibodies in achieving rapid pruritus reduction in adults with moderate to severe atopic dermatitis [pg. 6, Section 4.1.1.1.3] in combination with the success of the off-label use of dupilumab in treating PN. Dupilumab is an anti-IL-4/IL-13 antibody used for treating moderate to severe atopic dermatitis. When dupilumab was administered to patients with PN without any atopic dermatitis history, including patients administered prior therapies (e.g., corticosteroids), the PN was resolved [pg. 4, col. 2].
Therefore, it would have been obvious to one of ordinary skill in the art that the treatment method disclosed by the copending application could be applied to adult patients with prurigo nodularis as evidenced by Müller that teaches the identical IL-13 inhibitor (lebrikizumab) as a promising treatment for prurigo nodularis. One would have a reasonable expectation of success in administering to a patient the dosing regimen of lebrikizumab recited in the copending application as evidenced by Müller that teaches the dupilumab dosing regimen used for treating atopic dermatitis was successfully adopted in treating PN in pediatric and elderly patients [pg. 4, col. 1, par. 2]. Therefore, the combination of prior art elements according to known methods would be expected to yield predictable results with a reasonable expectation of success.
This is a provisional nonstatutory double patenting rejection.
Conclusion
No claim is allowed.
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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/MAUREEN VARINA DRISCOLL/ Examiner, Art Unit 1642
/SAMIRA J JEAN-LOUIS/Supervisory Patent Examiner, Art Unit 1642
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