DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
The amendment filed on 4/7/2026 amended claims 11 and 17-19, cancelled claims 12, 14, and 20, and added new claims 41-48. Claims 1-10 and 21-40 were previously cancelled. Claims 11, 13, 15-19, and 41-48 are pending and will be examined on the merits.
Response to Amendment
The amendment filed 4/7/2026 in response to the office action mailed 1/9/2026 is acknowledged. The objections and the rejections set forth under 35 USC 112 and 102 are withdrawn for the following reasons:
The objections have been rectified by the amendment. The 112(b) rejection has been rendered moot by the cancellation of claim 20. The 112(a) written description rejection and the 102 rejection are withdrawn in light of the amendments to claim 11.
Maintained or modified rejections are set forth below, as necessitated by the amendments. Responses to arguments follow.
Claim Objections
Claim 48 is objected to because of the following informalities: Claim 48 recites "the therapeutic method according to claim. Appropriate correction is required.
Maintained Claim Rejections - 35 USC § 103 - Modified as Necessitated by Claim Amendments
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claims 11, 15-18, and 42-46 are rejected under 35 U.S.C. 103 as being unpatentable over Back et al., WO 2019/229155 A1, 2019 (hereinafter known as Back) in view of Papp et al., JEADV (2017); 31:1324-1332 (hereinafter Papp).
Claim 11 describes a therapeutic method for an atopic dermatitis disease including subcutaneously administering an anti-OX40 antibody with the recited sequences to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 15-18 and 45-46 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent. Claims 42-44 further recite the constant regions and the full length sequences for the heavy and light chains of the anti-OX40 antibody.
Back teaches a therapeutic method for atopic dermatitis (see page 5, lines 4-5 and 9) that includes subcutaneous administration of an anti-OX40 antibody to a patient at a dose of 300 mg once every two weeks continuously at the same dose in Example 3 (see table 85), teaching the method recited in claims 11, 15-16, and 45-46. The therapeutic method of Back is administered to patients with moderate to severe atopic dermatitis which is poorly controllable using topical agents (Example 3, page 109, line 11), as recited in claims 11, 17, and 18. Additionally, Back teaches the absolute bioavailability of the tested anti-OX40 antibody GBR830 (page 104 line 3).
Back does not teach the use of the specific antibody of claim 11.
Papp teaches the use of the anti-OX40 antibody of claim 11, in treatment of plaque psoriasis, another autoimmune skin disease. Papp compares IV administration of the antibody of claim 11, referred to as KHK4083 in both the instant specification and Papp, with subcutaneous (SC) administration. KHK4083 is recited in the instant specification to have the amino acid sequences of SEQ ID NOs 1 and 2 as the respective VH and VL, SEQ ID NOs 3 and 4 as the respective heavy and light chain constant regions, and SEQ ID NOs 5 and 6 as the respective full length heavy and light chain sequences. Therefore, the antibody of Papp also meets the limitations of instant claims 42-44. Papp showed a greater response when the antibody was SC administered (page 1332 left column), providing a strong indication that SC administration of KHK4083 is more advantageous than IV administration. As a first-in-human study of this antibody, Papp calls for further testing using repeated doses via SC administration of KHK4083. Papp also teaches the bioavailability for KHK4083 after SC administration is higher than that taught by Back (page 1332 left column).
Taking this information together, a person of ordinary skill in the art of atopic dermatitis treatment, before the effective filing date of the invention, would have been motivated to combine the method of Back with the antibody of Papp. The antibody of Papp has a higher absolute bioavailability than then antibody of Back, which is defined as “the proportion of a drug or other substance which enters the circulation when introduced into the body and so is able to have an active effect.” With the knowledge there is more antibody available when the antibody of Papp is administered, one skilled in the art would be motivated to substitute the antibody of Papp in place of the antibody of Back, as the antibodies target the same receptor.
Additionally, the administration method of Back provides higher, repeated doses for the SC administration of anti-OX40 antibodies, as called for by Papp. Applying the method of Back to the antibody of Papp would have been obvious to one skilled in the art of antibody treatment, as the antibodies target the same molecule and extended administration is indicated in Papp.
Finally, atopic dermatitis and plaque psoriasis are both autoimmune skin diseases known to be mediated by OX40, and indeed, Back names plaque psoriasis as an “OX40-mediated disease” on page 29, line 15.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date to use the antibody of Papp with the administration method of Back to treat atopic dermatitis.
Claims 11, 13, 15-18, and 42-26 are rejected under 35 U.S.C. 103 as being unpatentable over Back in view of Papp as applied to claims 11, 15-18, and 42-46 above, and further in view of Blauvelt et al., Lancet (2017); 389:2287-303 (hereinafter Blauvelt).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 15-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent. Claim 13 is drawn to extending the method of claim 11 for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks or 34 weeks after starting the administration.
The teaching of Back in view of Papp regarding claims 11, 15-18, and 42-46 are recited above, under paragraph 6. Neither Papp nor Back teach the administration of this therapeutic method for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks, or 34 weeks after starting the administration, as stated in instant claim 13.
Blauvelt teaches the treatment of atopic dermatitis with a different antibody (dupilumab) every 2 weeks at a dose of 300 mg, with administration continuing for 52 weeks. Blauvelt explains that the 52-week duration of the study allowed the antibody to treat atopic dermatitis (AD) flares over time, a common AD disease manifestation. Blauvelt shows that the administration of the antibody reduced flare rates and fewer patients experienced adverse events of AD exacerbation (Page 2300, left column, paragraph 3).
Therefore, one of ordinary skill in the art of atopic dermatitis treatment, based on the teachings of Blauvelt, would be motivated to extend the treatment of Back for at least 16, 20, 22, 24, or 36 weeks, as in instant claim 13, because Blauvelt has demonstrated that longer administration of antibody treatment results in more positive patient outcomes, such as reduced flare rates and fewer adverse events. Thus, it would have been prima facie obvious to one of ordinary skill of the art before the effective filing date of the invention to combine the administration method of Back and the length of administration of Blauvelt to improve patient outcomes.
Claims 11, 13, 15-19, and 41-46 are rejected under 35 U.S.C. 103 as being unpatentable over Back in view of Papp as applied to claims 11, 15-18, and 42-46 above, and further in view of Lin et al., WO 2018/057849 A1, 2018 (hereinafter known as Lin).
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 15-18 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent. Claim 13 is drawn to extending the method of claim 11 for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks or 34 weeks after starting the administration. Claim 19 further limits claim 11 with the combination of this therapeutic method with a topical agent such as a steroid. Claim 41 further limits claim 19, reciting the topical agent is a corticosteroid, a calcineurin inhibitor or a combination thereof. Claims 47 and 48 recite alterations in the method of claim 11, with claim 47 reciting administration of the method of claim 11, which includes administering the antibody once every 4 weeks, for 16 or 24 weeks, then once every 4 or 8 weeks, and claim 48 reciting the antibody initially administered once every 2 weeks, then lengthened to once every 4 weeks.
The teaching of Back in view of Papp regarding claims 11, 15-18, and 42-46 are recited above, under paragraph 6. Neither Papp nor Back teach the administration of this therapeutic method for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks, or 34 weeks after starting the administration, as stated in instant claim 13, or the combination of this therapeutic method and a known topical agent, such as a corticosteroid, as in instant claims 19 and 41.
Lin teaches a method of treating atopic dermatitis in a patient, the method comprising subcutaneously administering to the patient 250 mg of an anti-IL-13 antibody once every four weeks (see claim 14). Lin also teaches that the antibody is administered for 24 weeks or more (See claim 16). Lin also teaches the administration of the antibody therapy combined with a topical corticosteroid (see claims 105 and 106 of Lin). Therefore, Lin teaches the limitations of claims 13, 19, and 41 that Back and Papp do not teach.
Paragraphs [00235-7] of Lin discuss the results of a trial of treatment of atopic dermatitis patients for 12 weeks at a dose of 125 mg; the results of this trial indicate that extended treatment at a higher dose would provide for better patient outcomes. Paragraph [00237] explicitly states that there is improved efficacy with increased dose and duration of treatment, and states that administering the antibody every four weeks at a dose of 250 mg would lead to increased efficacy, a statement further supported in the following examples, paragraphs [00250-1]. Moreover, paragraphs [00238-00239] of Lin state that application of a topical corticosteroid (referred to as TCS) in addition to antibody therapy was incorporated into this study to improve patient compliance in the control arm, and provides support that the inclusion of TCS improved patient participation in the placebo arm of the study. Lin points out that there was a high compliance rate, of 88%, to TCS administration in all treatment groups of the study. Lin also shows improvement in study results across all arms of the study, with an increased improvement rate when antibody therapy was combined with TCS usage, which indicates that TCS administration improves patient outcomes.
Taken together, prior to the effective filing date of the instant application, one of ordinary skill in the art of atopic dermatitis treatment would have been motivated to modify the administration method of the anti-OX40 antibody of Back with the dosing schedule of Lin. As Lin teaches that antibody treatment of atopic dermatitis has improved efficacy with increased dose of antibody and treatment duration, one would be motivated by that knowledge to use the treatment method of Back, with the antibody of Papp, for an extended amount of time. Moreover, the beneficial outcomes outlined in Lin would motivate one skilled in the art of antibody treatment of atopic dermatitis to use the specific treatment schedules outlined in Lin. Additionally, one of ordinary skill in the art of atopic dermatitis treatment would have been motivated to include the administration of a topical agent, such as the topical corticosteroid of Lin, in order to increase patient compliance and decrease patient dropout in their study, as well as to improve patient outcomes, as seen in Lin. One would have a reasonable expectation of success when combining these methods, as they have been successful in other atopic dermatitis treatment trials.
Therefore, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filing date of the invention to combine the therapeutic method of Back in view of Papp with the dosing schedule of Lin and the administration of a TCS as indicated by Lin to improve patient outcomes and treatment efficacy.
Response to Arguments
Applicant's arguments filed 4/7/2026 have been fully considered but they are not persuasive. Applicant argues that Papp does not teach the method of claim 1 as recited by the present claim. Applicant argues that plaque psoriasis is not similar to atopic dermatitis, as they are driven by different types of inflammation (Th17-mediated vs Th2-mediated), and so the treatment of psoriasis in Papp does not indicate a reasonable expectation of success. Applicant also argues unexpected results over Back.
In response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986). Papp is not intended to teach “treating an atopic dermatitis disease by ‘subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg 10 600 mg once in two weeks to four weeks continuously at the same dose’ as recited by the present claims”; the combination of Papp with the method of Back teaches this.
In response to applicant's argument that Papp is nonanalogous art, it has been held that a prior art reference must either be in the field of the inventor’s endeavor or, if not, then be reasonably pertinent to the particular problem with which the inventor was concerned, in order to be relied upon as a basis for rejection of the claimed invention. See In re Oetiker, 977 F.2d 1443, 24 USPQ2d 1443 (Fed. Cir. 1992). In this case, both psoriasis and atopic dermatitis would be treated by a dermatologist; therefore, one treating the instant disease would likely be aware of the treatment options for psoriasis as well. Moreover, OX40 is implicated in both atopic dermatitis and in psoriasis, as recited in the instant specification (paragraph [0071]), the specification of Back (page 29, lines 14-29), the introduction of Papp (third paragraph, page 1325), and the introduction of Nakagawa (second paragraph, right column, page 82). One skilled in the art of antibody treatment of autoimmune mediated skin diseases would know that the same target has been implicated in both diseases, and would be motivated to try treatments that worked in one disease (psoriasis) on the other (atopic dermatitis), as the treatment targets a molecule that has been implicated in both conditions. Therefore, one skilled in the art would find Papp reasonably pertinent to anti-OX40 atopic dermatitis treatment, such as Back.
Moreover, the justification of using the antibody of Papp as it has higher bioavailability than that of Back would stand regardless of the disease treated, as neither AD or psoriasis would affect the availability of the antibody. Therefore, Applicant’s argument that Papp is not analogous art is found unpersuasive.
Applicant argues unexpected results. As stated in the MPEP 716.02(d),
“Whether the unexpected results are the result of unexpectedly improved results or a property not taught by the prior art, the "objective evidence of nonobviousness must be commensurate in scope with the claims which the evidence is offered to support." In other words, the showing of unexpected results must be reviewed to see if the results occur over the entire claimed range. In re Clemens, 622 F.2d 1029, 1036, 206 USPQ 289, 296 (CCPA 1980); In re Grasselli, 713 F.2d 731, 741, 218 USPQ 769, 777 (Fed. Cir. 1983).” (emphasis added).
Applicant compares the EASI75 results of the clinical trial proposed in Back, stated in Exhibit A, with the EASI75 results provided in the instant specification. The results from Back include those from the groups administered 300 mg every 2 weeks, and 600 mg administered every 2 weeks. The results from the instant application that are compared to Back are from the group administered 300 mg every 2 weeks. The results outlined are persuasive for the provided comparison. However, the instant claims are drawn more broadly than just 300 mg every 2 weeks – claim 11 includes any dose from 150 mg-600 mg administered every 2-4 weeks. The results of decreased itching, seen in groups administered 300 mg Q2W and 600 mg Q2W or Q4W, is also not commensurate with the scope of the claims. As “the objective evidence of nonobviousness must be commensurate in scope with the claims”, as recited in the MPEP, this evidence is not convincing, as the results do not occur over the entire claimed range.
Taken together, Applicant’s arguments regarding the 103 rejection are not convincing, and the rejection stands.
New 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 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.
Claim(s) 11, 13, 15-18, and 42-48 is/are rejected under 35 U.S.C. 103 as being unpatentable over NCT03131648 (ECZTRA 1) in view of Nakagawa et al., 2020.
Claim 11 describes a therapeutic method for an OX40-related immune- or allergy-related disease including subcutaneously administering an anti-OX40 antibody to a patient at a dose of 150 mg to 600 mg once in two weeks to four weeks continuously at the same dose, with claims 15-18 and 45-46 further specifying variations in the 2-4 week window and the 150-600 mg dose, as well as the application of the therapeutic method to cases of moderate to severe atopic dermatitis which is poorly controllable using a topical agent. Claims 42-44 further recite the constant regions and the full length sequences for the heavy and light chains of the anti-OX40 antibody. Claim 13 is drawn to extending the method of claim 11 for at least 16 weeks, 20 weeks, 22 weeks, 24 weeks or 34 weeks after starting the administration. Claims 47 and 48 recite alterations in the method of claim 11, with claim 47 reciting administration of the method of claim 11, which includes administering the antibody once every 4 weeks, for 16 or 24 weeks, then once every 4 or 8 weeks, and claim 48 reciting the antibody initially administered once every 2 weeks, then lengthened to once every 4 weeks.
Nakagawa teaches the use of the anti-OX40 antibody of claim 11, in treatment of moderate to severe atopic dermatitis (page 83, section “2. Materials and methods”, left column). Nakagawa teaches IV administration of the antibody of claim 11, referred to as KHK4083 in both the instant specification and Nakagawa, every 2 weeks for 6 weeks (page 83, right column section “2.2 Study design”). KHK4083 is recited in the instant specification to have the amino acid sequences of SEQ ID NOs 1 and 2 as the respective VH and VL, SEQ ID NOs 3 and 4 as the respective heavy and light chain constant regions, and SEQ ID NOs 5 and 6 as the respective full length heavy and light chain sequences. Therefore, the antibody of Nakagawa also meets the limitations of instant claims 42-44.
Nakagawa indicates that the KHK4083 antibody is antagonistic to OX40 activity and an effective treatment in human patients with atopic dermatitis. Nakagawa does not teach a method of subcutaneous administration, or administration continued for more than 16 weeks, a flat dose of 150 mg or 300 mg, or administering once every 4 or 8 weeks after 16 or 24 weeks.
NCT03131648 teaches a clinical trial for the treatment of moderate-to severe atopic dermatitis, poorly controlled by topical treatments, that comprises administering an antibody at a dose of 300 mg every 2 weeks, for 16 weeks, then administering the antibody at a dose of 300 mg every 4 weeks (see Protocol for NCT03131648, page 32-33). NCT03131648 uses this extended treatment period, or ‘maintenance therapy’, because AD is a chronic disease requiring long term treatment. NCT03131648 uses an anti-IL-13 antibody and not an anti-OX40 antibody.
While NCT03131648 and Nakagawa use different antibodies, they are both used in the treatment of atopic dermatitis. Indeed, the introduction of Nakagawa recites the importance of Th2 immune responses in atopic dermatitis, and indicates inhibiting the OX40 signaling pathway as a potential treatment target for AD. Moreover, the discussion of Nakagawa recites, on page 88, left column, third paragraph, that KHK4083 inhibited inflammation and Th2 cell infiltration, thereby interrupting the aggravated Th2 mediated inflammation responsible for many AD symptoms. The protocol for NCT03131648 also emphasizes the importance of the Th2 pathway on page 30, and details that the anti-IL-13 antibody prevents activation of Th2 immune responses, similar to an anti-OX40 antibody. Therefore, as anti-IL-13 antibodies and anti-OX40 antibodies impact the same root cause of inflammation responsible for AD, one of ordinary skill in the art would be aware of the dosing protocols and administration of both anti-OX40 and anti-IL-13 antibodies. As the anti-IL-13 antibody has been administered in more clinical trials (see Protocol, page 31) for atopic dermatitis, there is more information about the administration patterns of this antibody than any anti-OX40 antibody. Therefore, one of ordinary skill in the art of antibody treatment of atopic dermatitis would be motivated to use the treatment protocol outlined in NCT03131648 to administer the anti-OX40 antibody of Nakagawa for a longer period of time. One would be motivated to so do as the antibody of Nakagawa is shown to be effective in AD treatment (see Nakagawa figures 2 and 3), but with adverse effects due to IV administration (see Table 2 and page 87, left column, last paragraph); subcutaneous administration, as in NCT03131648, would prevent these adverse effects. Additionally, one would be motivated to continue the treatment for longer than the 6 weeks in Nakagawa because the antibody is known to be safe (Section 3.3, page 84, Table 2), and, as recited in the protocol for NCT03131648, AD is a chronic disease requiring long term treatment. Therefore, one of ordinary skill in the art would be motivated to use long term administration schedules that are known in the art, such as the one of NCT03131648, to extend treatment of AD with the antibody of Nakagawa. Finally, KSR International Co. v. Teleflex Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007), discloses that if a method is “obvious to try”, it is not patentable over the prior art. MPEP § 2144.05(II) recites that routine optimization is “obvious to try”, and therefore supported by said rational. Dosing parameters, such as how often a medication is administered, could be routinely optimized in light of other dosing protocols. Therefore, it would be obvious to routinely optimize the dosing protocol of NCT03131648 or other antibody regimens for atopic dermatitis for the KHK4083 antibody disclosed in Nakagawa to optimize AD antibody treatment and provide optimal reduction of symptoms. Thus, the combination of prior art references as combined provided a prima facie case of obviousness, absent convincing evidence to the contrary. As a result, claims 11, 13, 15-18, and 42-48 are rejected under USC 103 as obvious over Nakagawa in view of NCT03131648.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any 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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/AMELIA STEPHENS/ Examiner, Art Unit 1645
/ANNE M. GUSSOW/ Supervisory Patent Examiner, Art Unit 1683
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