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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on August 10, 2026 has been entered.
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 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over the Clinical Trial Listing NCT02277444 (Version Published: Nov 28, 2018) as evidenced by the instant Specification in view of Benedetti et al. (The New England Journal of Medicine. 367: 2385-2395; Published: December 20, 2012).
The Clinical Trial Listing for NCT02277444 teaches a method comprising treating juvenile idiopathic arthritis (JIA) in pediatric patients, the method comprising administering an intravenous (IV) dose of golimumab, an anti-TNF antibody, to the pediatric patient. As evidenced by the instant Specification, golimumab comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO:36 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:37; see page 1, lines 19-21 of the instant disclosure. The IV dose is 80mg/m2 of the anti-TNF antibody, at weeks 0, 4, and then every 8 weeks thereafter; see Arms and Interventions.
Regarding claims 2 and 3, the pediatric patients enrolled in NCT02277444 are 2 to <18 years old and have been diagnosed with juvenile idiopathic arthritis (JIA) is polyarticular juvenile idiopathic arthritis (pJIA).
Regarding claim 5, the method further comprises administering methotrexate (MTX) to the pediatric patients.
Regarding the treatment period in claim 1, treatment could be administered for up to 244 weeks with outcome measures assessed through week-52.
Regarding the results of said treatment as recited in claim 1, a method cannot be separated from its inherent outcome (see the entire document).
The Clinical Trial Listing for NCT02277444 does not teach a step of measuring whether the pediatric patient has achieved sustained improvement after 52 weeks nor of determining that the patient is a response by achieving the measure of sustained improvement.
Benedetti et al. teaches a clinical trial of tocilizumab in juvenile idiopathic arthritis. Benedetti et al. teaches assessing the proportion of patients who had a JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response; see page 2387 left column.
It would have been obvious to one of ordinary skill in the art to measure JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52, which is the same time frame for measuring pharmacokinetics in the Clinical Trial Listing for NCT02277444. One would have been motivated to modify the Clinical Trial Listing for NCT02277444 to add the JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response measures through week 52 in order to compare efficacy with other biologics competing for market share in the juvenile idiopathic arthritis space. One would have had a reasonable expectation of success measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52 because Benedetti et al. teaches measuring the same efficacy metrics in the same time frame for another biologic therapy in juvenile idiopathic arthritis. Regarding the step of determining that a patient is a responder by achieving the measure of sustained improvement necessarily flows from the step of measuring. Indeed, one measuring whether a patient achieved a sustained improvement, in doing so, is determining that a patient is a responder based on the patient having achieved one of the metrics recited. The instant Specification evidences that the outcome inherent to the step of administering the TNF-antibody comprising SEQ ID NOs: 36 and 37 intravenously to patients having juvenile idiopathic arthritis is 70% and 47% of patients achieving JIA ACR 70 or JIA ACR 90, respectively, with response rates maintained through week 52; see page 201.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Leu et al. (Clinical Pharmacology in Drug Development. 8(S1): 1–101; Published: August 21, 2019) as evidenced by the instant Specification in view of Benedetti et al. (The New England Journal of Medicine. 367: 2385-2395; Published: December 20, 2012).
Leu et al. teaches treating juvenile idiopathic arthritis (JIA) in pediatric patients, the method comprising administering an intravenous (IV) dose of golimumab, an anti-TNF antibody, to the pediatric patient; see Statement of Purpose, Innovation or Hypothesis section on page 28. As evidenced by the instant Specification, golimumab comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO:36 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:37; see page 1, lines 19-21 of the instant disclosure. The IV dose is 80mg/m2 of the anti-TNF antibody, at weeks 0, 4, and then every 8 weeks thereafter; see Description of Methods and Materials section.
Regarding claims 2 and 3, the pediatric patients treated were 2 to <18 years old and had been diagnosed with juvenile idiopathic arthritis (JIA) or polyarticular juvenile idiopathic arthritis (pJIA); see Statement of Purpose, Innovation or Hypothesis section on page 28.
Regarding claim 5, the method further comprises administering methotrexate (MTX) to the pediatric patients; see Description of Methods and Materials sections on page 29.
Regarding the treatment period in claim 1, treatment could be administered for up to 244 weeks with outcome measures assessed through week-52. Leu et al. teaches that JIA ACR 30, 50, 70 and 90 response rates were measured; see Data and Results section on page 29.
Regarding the results of said treatment as recited in claim 1, a method cannot be separated from its inherent outcome (see entire Leu et al. Abstract).
Leu et al. does not teach a step of measuring whether the pediatric patient has achieved sustained improvement after 52 weeks nor of determining that the patient is a response by achieving the measure of sustained improvement.
Benedetti et al. teaches a clinical trial of tocilizumab in juvenile idiopathic arthritis. Benedetti et al. teaches assessing the proportion of patients who had a JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response; see page 2387 left column.
It would have been obvious to one of ordinary skill in the art to measure JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52, which is the same time frame for measuring pharmacokinetics in Leu et al. One would have been motivated to modify Leu et al. to add the JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response measures through week 52 in order to compare efficacy with other biologics competing for market share in the juvenile idiopathic arthritis space. One would have had a reasonable expectation of success measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52 because Benedetti et al. teaches measuring the same efficacy metrics in the same time frame for another biologic therapy in juvenile idiopathic arthritis. Regarding the step of determining that a patient is a responder by achieving the measure of sustained improvement necessarily flows from the step of measuring. Indeed, one measuring whether a patient achieved a sustained improvement, in doing so, is determining that a patient is a responder based on the patient having achieved one of the metrics recited. The instant Specification evidences that the outcome inherent to the step of administering the TNF-antibody comprising SEQ ID NOs: 36 and 37 intravenously to patients having juvenile idiopathic arthritis is 70% and 47% of patients achieving JIA ACR 70 or JIA ACR 90, respectively, with response rates maintained through week 52; see page 201.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Claims 1-3 and 5 are rejected under 35 U.S.C. 103 as being unpatentable over Ruperto et al. (Annals of the Rheumatic Diseases. 78(2): FRI0543; Published: June 1, 2019) as evidenced by the instant Specification in view of Clinical Trial Listing NCT02277444 (Version Published: Nov 28, 2018) and Benedetti et al. (The New England Journal of Medicine. 367: 2385-2395; Published: December 20, 2012).
Ruperto et al. teaches treating juvenile idiopathic arthritis (JIA) in pediatric patients, the method comprising administering an intravenous (IV) dose of golimumab, an anti-TNF antibody, to the pediatric patient; see Methods section. As evidenced by the instant Specification, golimumab comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO:36 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:37; see page 1, lines 19-21 of the instant disclosure. The IV dose is 80mg/m2 of the anti-TNF antibody, at weeks 0, 4, and then every 8 weeks thereafter; see Methods section.
Regarding claims 2 and 3, the pediatric patients treated were 2 to <18 years old and had been diagnosed with juvenile idiopathic arthritis (JIA) or polyarticular juvenile idiopathic arthritis (pJIA); see Methods section.
Regarding claim 5, the method further comprises administering methotrexate (MTX) to the pediatric patients; see Methods section.
Ruperto et al. teaches that JIA ACR 30, 50, 70 and 90 response rates were measured at week 28; see Results section.
Regarding the results of said treatment as recited in claim 1, a method cannot be separated from its inherent outcome (see entire Ruperto et al. Abstract).
Ruperto et al. does not teach treating for 52 weeks nor a step of measuring whether the pediatric patient has achieved sustained improvement after 52 weeks or of determining that the patient is a response by achieving the measure of sustained improvement.
Like Ruperto et al., the Clinical Trial Listing for NCT02277444 teaches a method comprising treating juvenile idiopathic arthritis (JIA) in pediatric patients, the method comprising administering an intravenous (IV) dose of golimumab, an anti-TNF antibody, to the pediatric patient. As evidenced by the instant Specification, golimumab comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO:36 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:37; see page 1, lines 19-21 of the instant disclosure. The IV dose is 80mg/m2 of the anti-TNF antibody, at weeks 0, 4, and then every 8 weeks thereafter; see Arms and Interventions. Treatment could be administered for up to 244 weeks with outcome measures assessed through week-52.
Neither Ruperto et al. nor the Clinical Trial Listing for NCT02277444 teach a step of measuring whether the pediatric patient has achieved sustained improvement after 52 weeks or of determining that the patient is a response by achieving the measure of sustained improvement.
Benedetti et al. teaches a clinical trial of tocilizumab in juvenile idiopathic arthritis. Benedetti et al. teaches assessing the proportion of patients who had a JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response; see page 2387 left column.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to continue the treatment taught by Ruperto et al. through week 52 as taught by t the Clinical Trial Listing for NCT02277444. One would have been motivated to continue treating past the 28 weeks described in Ruperto et al. because Benedetti et al. described JIA as a chronic condition; see Introduction. Additionally, it would have been obvious to one of ordinary skill in the art to measure JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52. One would have been motivated to modify Ruperto et al. to add the JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response measures through week 52 into to compare efficacy with other biologics competing for market share in the juvenile idiopathic arthritis space. One would have had a reasonable expectation of success measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52 because Benedetti et al. teaches measuring the same efficacy metrics in the same time frame for another biologic therapy in juvenile idiopathic arthritis. Regarding the step of determining that a patient is a responder by achieving the measure of sustained improvement necessarily flows from the step of measuring. Indeed, one measuring whether a patient achieved a sustained improvement, in doing so, is determining that a patient is a responder based on the patient having achieved one of the metrics recited. The instant Specification evidences that the outcome inherent to the step of administering the TNF-antibody comprising SEQ ID NOs: 36 and 37 intravenously to patients having juvenile idiopathic arthritis is 70% and 47% of patients achieving JIA ACR 70 or JIA ACR 90, respectively, with response rates maintained through week 52; see page 201.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
Double Patenting
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 1-3 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3-7, 11-16, and 18-21 of copending Application No. 17/423,177 in view of Benedetti et al. (The New England Journal of Medicine. 367: 2385-2395; Published: December 20, 2012) and the Clinical Trial Listing NCT02277444 (Version Published: Nov 28, 2018) as evidenced by the instant Specification.
Regarding instant claim 1, copending claims 1, 7, and 15 teach administering an intravenous dose of an anti-TNF antibody comprising the heavy chain and light chains comprising SEQ ID NOs: 36 and 37, respectively, to pediatric patients having JIA. Copending SEQ ID NOs: 36 and 37 are 100% identical to instant SEQ ID NOs: 36 and 37, respectively.
Regarding the outcomes of instant claim 1 (a) – (d), copending claims 1, 7, 15, and 16 teach the outcomes of achieving: (a) JIA ACR 30, 50, and/or 70, (b) JADAS 71 minimal or low disease activity, and (c) inactive disease.
Regarding instant claims 2 and 3, copending claims 3, 4, 11, 12, 18, and 19 teach treating the same patient population.
Regarding the dosing of the anti-TNF antibody and the use of methotrexate in instant claims 1 and 5, copending claims 5, 6, 13, 14, 20, and 21 teach the same dosing regimen and combination partner.
While the copending claims teach measuring efficacy through week 28, they do not teach a step of measuring whether the pediatric patient has achieved sustained improvement after 52 weeks nor of determining that the patient is a response by achieving the measure of sustained improvement. Additionally, the copending claims do not teach treating through week 52.
The Clinical Trial Listing for NCT02277444 teaches a method comprising treating juvenile idiopathic arthritis (JIA) in pediatric patients, the method comprising administering an intravenous (IV) dose of golimumab, an anti-TNF antibody, to the pediatric patient. As evidenced by the instant Specification, golimumab comprises a heavy chain (HC) comprising an amino acid sequence of SEQ ID NO:36 and a light chain (LC) comprising an amino acid sequence of SEQ ID NO:37; see page 1, lines 19-21 of the instant disclosure. The IV dose is 80mg/m2 of the anti-TNF antibody, at weeks 0, 4, and then every 8 weeks thereafter; see Arms and Interventions. Treatment could be administered for up to 244 weeks with outcome measures assessed through week-52.
The Clinical Trial Listing for NCT02277444 does not teach measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52.
Benedetti et al. teaches a clinical trial of tocilizumab in juvenile idiopathic arthritis. Benedetti et al. teaches assessing the proportion of patients who had a JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response; see page 2387 left column.
It would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success to continue treating JIA beyond week 28 through week 52 because the Clinical Trial Listing for NCT02277444 teaches treating through week 52 and Benedetti et al teaches that JIA is a chronic condition. It would have been obvious to one of ordinary skill in the art to measure JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52. One would have been motivated to modify the method of the copending claims to add the JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response measures through week 52 into to compare efficacy with other biologics competing for market share in the in juvenile idiopathic arthritis space. Further, since Benedetti et al. teaches that juvenile idiopathic arthritis is a chronic disease (see Introduction), one would have been motivated to assess efficacy for a treatment duration of minimally through a year given that patients will require long-term therapy. One would have had a reasonable expectation of success measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, or JIA ACR 90 response through week 52 because Benedetti et al. teaches measuring the same efficacy metrics in the same time frame for another biologic therapy in juvenile idiopathic arthritis. Regarding the step of determining that a patient is a responder by achieving the measure of sustained improvement necessarily flows from the step of measuring. Indeed, one measuring whether a patient achieved a sustained improvement, in do so, is determining that a patient is a responder based on the patient having achieved one of the metrics recited. The instant Specification evidences that the outcome inherent to the step of administering the TNF-antibody comprising SEQ ID NOs: 36 and 37 intravenously to patients having juvenile idiopathic arthritis is 70% and 47% of patients achieving JIA ACR 70 or JIA ACR 90, respectively, with response rates maintained through week 52; see page 201.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art
before the effective filing date of the application, as evidenced by the references.
This is a provisional nonstatutory double patenting rejection.
Response to Arguments
Applicant’s amendments filed August 10, 2026 are acknowledged.
Applicant’s arguments filed August 10, 2026 have been fully considered and are persuasive in part.
Regarding the three rejections under 35 U.S.C. 103, applicant asserts that the primary reference (i.e. the Clinical Trial Listing NCT02277444, Leu et al., or Ruperto et al.) teach treating juvenile idiopathic arthritis with an IV dose of 80mg/m2 at week 0, 4, then Q8W thereafter, of golimumab, the anti-TNF antibody comprising instant SEQ ID NOs: 36 and 37. The primary references teach treating for at least 52 weeks, but do not provide efficacy data at or beyond 52 weeks. Leu et al. provides PK data as of week 28 and states that the “[p]harmacokinetic exposures were maintained through Wk 52. Consistently high JIA ACR 30, 50, 70 and 90 response rates were observed across the trough serum golimumab concentration quartiles”; see Data and Results. It is unclear whether the consistently high JIA ACR 30, 50, 70 and 90 response rates in Leu et al. are as of week 28 or week 52. Ruperto et al. teaches that the “[p]roportion of JIA ACR 30, 50, 70, & 90 responders at Wk28 was 83.5%, 79.5%, 70.1%, & 46.5%, respectively. 29.1% of patients met criteria for inactive disease at Wk28”; see Results. Benedetti et al. is relied upon as a secondary reference in all three rejections under 35 U.S.C. 103 for teaching measuring JIA ACR 30, JIA ACR 50, JIA ACR 70, and JIA ACR 90 responses at week 52 in JIA patients treated with an anti-IL-6 antibody.
Applicant argues that there is no reasonable expectation of success treating through week 52. In other words, that there is no reasonable expectation that efficacy data from week 28 taught in Leu et al. or Ruperto et al. would continue through week 52.
First, MPEP 2107.03 IV states [emphasis added] that, “as a general rule, if an applicant has initiated human clinical trials for a therapeutic product or process, Office personnel should presume that the applicant has established that the subject matter of that trial is reasonably predictive of having the asserted therapeutic utility.” On page 10 of the remarks, Applicant states that this section of the MPEP is only relevant to rejections under 35 U.S.C. 101 – not to rejections under 35 U.S.C. 103. The MPEP is clear that the presumption of reasonably predictive utility is a general rule.
Applicant has provided three references related to treating with TNF inhibitors or anti-TNF antibodies. The first is Billioud et al. which teaches that roughly 20% of patients treated with the anti-TNF antibody adalimumab for Crohn’s disease will experience a loss of response and highlights the significance of anti-drug antibodies in the loss of response.
The next to references Carrim et al. (2026) and Mannion et al. (2021) are not probative – MPEP 2143.02 III. states that predictability is determined at the relevant time and “the relevant time is ‘before the effective filing date of the claimed invention.’” Both Carrim et al. and Mannion et al. are both published after the effective filing date of Maril 27, 2020.
Nonetheless, Carrim et al. provides analysis of JIA patients being treated with the anti-TNF antibody, adalimumab, and the development of anti-drug antibodies and loss of response. Carrim et al. stratifies patients as having high or low anti-drug antibodies and Applicant highlights that 71% of patients having high anti-adalimumab antibody levels experience a loss of response in 12 months. This 71% statistic is limited to those which have high anti-adalimumab antibody levels, while the claims are to treating a singular pediatric patient – not required to have prior anti-TNF treatment. Carrim et al. teaches the distribution of JIA patients by anti-drug antibody and therapeutic antibody levels “we examined the combined effect of ADA_ab and ADA_drug by defining four groups: (i) ADA_ab: high, ADA_drug: therapeutic (16 patients), (ii) ADA_ab: high, ADA_drug: undetectable (19 patients), (iii) ADA_ab: low, ADA_drug: therapeutic (143 patients), (iv) ADA_ab: low, ADA_drug: undetectable (6 patients).”; see page 4 left column. Of the 184 patients examined, only 35 patients or 19% of patients presented with high anti-drug antibodies. Even if every patient presenting with high anti-drug antibodies develops loss of response, the resulting proportion of patients with loss of response would be roughly 20% - the same proportion taught in Billioud et al.
Next, Mannion et al. teaches that the median time to switching therapeutics among JIA patients being treated with a biologic, predominantly TNFis, is 7.2 months as of 2016 and down from 55.2 months in 2008. This statement is more a reflection of prescribing trends, likely resulting from more approved therapeutics. Mannion et al. indicates that more biologics have become available to JIA on page 1326 that “[w]hile switching medications was possible prior to this time [2008], the FDA approval of ADA and ABA allowed other biologics to be a standard option.”
The downward trend in months to first switch is reflected in the black trend line in the graph below. Of greater significance to the question of reasonable expectation of success, the lightest colored or leftmost bar of each triplet of bars represents the proportion of patients who did not switch. In 2017, that proportion of non-switchers was about 80%. Mannion et al. does state that the primary reason for switching among “immediate switchers”, represented by the medium gray, rightmost bars, is inefficacy; see Table 2. Yet, similar to Billioud et al. and Carrim et al., the proportion of “immediate switchers” was just below 20% in 2017.
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MPEP 2143.02 I. and II. state that “[c]onclusive proof of efficacy is not required to show a reasonable expectation of success” and “[o]bviousness does not require absolute predictability, but at least some degree of predictability is required.” The teaching of treating to through at least 52 weeks in an initiated human clinical trial provides the presumption of a reasonable expectation of success.
With respect to the references provided by Applicant, each teaches that roughly 20% of patients lose response to the anti-TNF antibody. The instant claims require treating a single pediatric patient having JIA. One of ordinary skill in the art would conclude that treating a single patient with an anti-TNF antibody would have a reasonable expectation of success of maintaining efficacy from week 28 through week 52, especially given that Billioud et al., Carrim et al., and Mannion et al. demonstrate that approximately 80% of patients do not experience of loss of response.
The rejection under 35 U.S.C. 103 over Ruperto et al. in view of Benedetti et al. is withdrawn. On page 8, Applicant argues that Ruperto et al. and Benedetti et al. teach treating with antibodies having different targets. Applicant highlights Benedetti et al. page 2386 where the reference teaches limited benefit of tumor necrosis factor inhibitors. This sentence cites references 5 and 6 which are about etanercept, a TNF receptor decoy fused to an Fc domain – a similar mechanism to instantly claimed golimumab. Applicant points to data in Tanaka et al. which indicates that golimumab, the instantly claimed antibody, would not be expected to have the same efficacy as tocilizumab, the agent taught in Benedetti et al. In fact, golimumab appears to be less efficacious than etanercept in the data of Tanaka et al.
Both Benedetti et al. and Ruperto et al. teach treating the same disease and Ruperto et al. already teaches treating through week 28 and measuring JIA ACR 30, 50, 70, and 90 at week 28. Benedetti et al. is relied upon for: 1. treating through week 52 and 2. measuring JIA ACR 30, 50, 70, and 90 through week 52. Given the reference to reduced efficacy of etanercept in Benedetti et al. and the demonstration that etanercept was less effective than tocilizumab, as taught by Benedetti et al., and more efficacious than golimumab, the instantly claimed antibody, one would not have had a reasonable expectation of success of achieving sustained improvement treating JIA with golimumab in place of tocilizumab through week 52.
Regarding the rejection under 35 U.S.C. 103 over the Clinical Trial Listing NCT02277444 in view of Benedetti et al., Applicant argues, on page 12, that no clinical results are published in the clinical trial listing before the effective filing date. MPEP 2143.02 I. states that “[c]onclusive proof of efficacy is not required to show a reasonable expectation of success”. Applicant argues that one would not have been motivated to combine the Clinical Trial Listing NCT02277444 and Benedetti et al. The Clinical Trial Listing NCT02277444 already teaches treating through week 52. Benedetti et al. is relied upon for measuring JIA ACR 30, 50, 70, and 90 through week 52. It would have been obvious to measure JIA ACR 30, 50, 70, and 90 through week 52 as taught by Benedetti et al. because the Clinical rial Listing NCT02277444 teaches treating through week 52 and both references teach the same indication – JIA. One would have had a reasonable expectation of efficacy through week 52 because the initiated human clinical trial teaches treating through week 52; see MPEP 2107.03 IV.
Regarding the rejection under 35 U.S.C. 103 over Leu et al. in view of Benedetti et al., Applicant argues, on page 16, that no clinical results are published in the clinical trial listing before the effective filing date. As above, conclusive proof of efficacy is not required to show a reasonable expectation of success; MPEP 2143.02 I. Applicant argues that Leu et al. does not teach measuring JIA ACR 30, 50, 70, and 90 through week 52 and that Benedetti et al. relates to an antibody that is different from Leu et al. and thus there would not be motivation to combine. However, Leu et al. teaches treating through week 52 and teaches measuring JIA ACR 30, 50, 70, and 90 through week 28. Benedetti et al. is relied upon for teaching measuring JIA ACR 30, 50, 70, and 90 through week 52. Both references teach measuring JIA ACR 30, 50, 70, and 90 and treating JIA with a biologic. It would have been obvious to one of ordinary skill in the art to continue measuring JIA ACR 30, 50, 70, and 90 through week 52 given that Benedetti et al. teaches measuring JIA ACR 30, 50, 70, and 90 through week 52 in JIA. Leu et al. teaches that “[c]onsistently high JIA ACR 30, 50, 70 and 90 response rates were observed across the trough serum golimumab concentration quartiles” and thus one would have had a reasonable expectation of success treating JIA with golimumab and measuring sustained improvement after 52 weeks JIA ACR 30, 50, 70, and 90.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure. The Clinical Trial Listing NCT01230827 (Version Published: Mar 31, 2016) and Results (Version Published: Apr 4, 2016) teaches treating JIA patients with multiple joint involvement (reads on polyarticular) by administering SC golimumab and methotrexate for a 48-treatment period and assessing the outcomes of claim 1 (a) – (d). Wallace et al. (The Journal of Rheumatology. 41: 1163-1170; Published: May 1, 2014) teaches that in polyarticular JIA achieving at least JIA ACR 70 at 4 months was a positive predictor of clinically inactive disease after 4 months; see Table 3 and Figure 2. Gerloni et al. (Arthritis & Rheumatism. 52(2): 548-553; Published: Feb 3, 2005) teaches treating polyarticular JIA by administering intravenous infliximab (anti-TNFα) and methotrexate for 1 year and measuring JIA ACR 20, JIA ACR 50, and JIA ACR 70.
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/GREGORY S EMCH/Supervisory Patent Examiner, Art Unit 1678
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