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 .
Claims Status
Claims 50, 57, and 72-75 are cancelled. Claims 76-80 are newly added. Claims 36, 42-43, 45-46, 52, 59-61, 63-64, 67, 71, 76-80 are pending and examined on the merits.
OBJECTIONS WITHDRAWN
Drawings
Receipt of replacement Figures 2-3 is acknowledged. Replacement Figure 1 was previously submitted 12/01/2021, and all objections to the drawings are withdrawn.
Specification
Objections to the specification regarding hyperlinks are withdrawn in view of applicant’s amendments.
NEW OBJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Objections
Claim 79 is objected to because of the following informalities:
Claim 79 is objected to for an apparent grammatical error. The claim recites the phrase “that is lower the starting dose” in line 4, which appears to be missing a word. The claim is interpreted to read “that is lower than the starting dose”, and this objection can be obviated by amending the claim as such.
Appropriate correction is required.
REJECTIONS MAINTAINED/UPDATED AS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 36, 42, 45, 61, 63-64, 67, and 71 remain rejected and Claims 52 and 79-80 are newly rejected under 35 U.S.C. 102 (a)(1) as being anticipated by Emery et al. 2008 (Annals of the rheumatic diseases, 67(11), 1516-1523.; IDS filed 02/26/2024), herein “Emery”.
Emery teaches a method of treating rheumatoid arthritis in patients refractory to tumor necrosis factor antagonist therapy comprising administering 8 mg/kg tocilizumab intravenously every 4 weeks (Abstract; Fig. 1).
Regarding Claims 36 and 67, Emery teaches that prior therapy at baseline was anti-TNF therapy (i.e. patients had not previously been administered tocilizumab) (Table 1).
Regarding Claims 36, 52, and 80, Emery teaches that the selected patients were 18 years or older (Pg. 1516, § Patients).
Regarding Claim 42, Emery teaches the rheumatoid arthritis is moderate to severe (Pg. 1516, § Patients).
Regarding Claim 45, Emery teaches that patients with inflammatory diseases other than rheumatoid arthritis (i.e. ankylosing spondylitis, Crohn’s disease, etc.) were excluded (pg. 1517, ¶1).
Regarding Claims 36 and 79, Emery teaches that 64.7% of the patients did not have anemia prior to tocilizumab treatment (Table 1, Baseline patient characteristics; 35.3% below lower limit of normal hemoglobin).
Regarding Claim 61, Emery teaches that patient is also administered methotrexate concomitant with the tocilizumab (Abstract; § Study Design “All patients received stable methotrexate (10–25 mg weekly)”).
Regarding Claims 63-64, Emery teaches the patients previously had an inadequate response to TNF antagonists (i.e. DMARDs) (Abstract, § Methods), including the biologics etanercept, adalimumab, and infliximab (Table 1).
Regarding Claim 71 Emery teaches 84% of patients were female (Table 1).
Claims 36, 42, 60, 67, and 71 remain rejected, and Claims 52 and 79-80 are newly rejected under 35 U.S.C. 102(a)(1) as being anticipated by Jones et al. 2010 (Annals of the rheumatic diseases, 69(1), 88-96.; IDS filed 02/26/2024), herein “Jones”.
Jones teaches a method of treating rheumatoid arthritis as a monotherapy comprising intravenous administration of 8 mg/kg of tocilizumab (Abstract; Fig. 1; § Study Protocol).
Regarding Claims 36 and 67, Jones teaches that at baseline the patients were previously treated with DMARDs, including methotrexate and anti-TNF agents (i.e. patients had not previously received tocilizumab) (Abstract; Table 1).
Regarding Claims 36, 52, and 80, Jones teaches the patients were 18 years or older (§ Patients, ¶1).
Regarding Claim 42, Jones teaches the rheumatoid arthritis is moderate to severe (§ Patients, ¶1).
Regarding Claims 36 and 79, Jones teaches that 62% of patients did not have anemia (Table 1; 38% below lower limit of normal hemoglobin).
Regarding Claim 60, Jones teaches tocilizumab was administered as a monotherapy (i.e. no concomitant DMARDs) and its efficacy was compared to patients receiving methotrexate monotherapy (Abstract; Fig. 1).
Regarding Claim 71, Jones teaches 83% of patients were female (Table 1).
Claims 36, 42, 45, 63-64, 67 and 71 remain rejected and Claims 52 and 80 are newly rejected under 35 U.S.C. 102(a)(1) as being anticipated by Burmester et al. (Annals of the rheumatic diseases, 73(1), 69-74.; IDS filed 02/26/2024), herein “Burmester”.
Burmester teaches a method of treating rheumatoid arthritis comprising administering a 162 mg subcutaneous dose of tocilizumab once every week (Abstract, § Study design).
Regarding Claims 36, 52, and 80, Burmester teaches the patients were 18 or older (§ Participants).
Regarding Claim 42, Burmester teaches the rheumatoid arthritis was moderate to severe (Title).
Regarding Claims 36 and 80, Burmester teaches patients were stratified by weight, with 23.5% <60 kg and 67% between 60-100 kg (§ Study design; Table 1). Burmester further teaches patients less than 100 kg exhibited a greater response to treatment (Pg. 71, ¶5).
Regarding Claim 45, Burmester teaches patients with rheumatic diseases other than rheumatoid arthritis were excluded (Pg. 70, ¶2).
Regarding Claims 63-64, Burmester teaches patients had inadequate response to previous DMARD therapy including methotrexate (Pg. 70, ¶1; Table 1; § Patient disposition and baseline characteristics, ¶3)
Regarding Claim 71, Burmester teaches 82.6% of patients were female (Table 1).
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive because:
Regarding the rejections made under Emery et al., Applicant argues that “the present application is directed to a method treating rheumatoid arthritis (RA) in a subgroup that can be started at the outset on a higher or “escalated” dose of TCZ (i.e., 162 mg of TCZ once per week subcutaneously, or 8 mg/kg of TCZ once every 4 weeks intravenously), rather than receiving a lower dose that is then escalated”.
However, Emery does not teach “a lower dose that is then escalated” but instead teaches a cohort of patients that were exclusively treated with intravenous TCZ at 8 mg/kg Q4W. None of the patients enrolled in the 8 mg/kg arm of the trial had received a prior lower dose of TCZ. Of the patients that were started at a dose of 8 mg/kg, many possessed the instantly claimed characteristics. For example, 64.7% were above the lower limit of normal for hemoglobin (i.e. not anemic; See Table 1).
Indeed, starting RA patients at the purportedly “escalated” TCZ dose encompassed by the instant claims is already in common practice. For example, Pappas et al. 2016 (Rheumatology and Therapy, 3(1), 103-115.; PTO-892) teaches that a subset of patients included in a retrospective dose escalation study of TCZ initiated treatment at dose of 8 mg/kg (Fig. 1), and further teaches that countries outside the United States, including European countries and Japan, recommend a starting dose of 8 mg/kg (Pg. 104, Col. 2, ¶2).
Use of the “escalated” subcutaneous 162 mg QW starting dose is similarly widespread. For example, Choy et a. 2017 (Rheumatology, 57(3), 499-507.; IDS dated 09/10/2025) teaches the TOZURA study which followed 1804 patients over two years, all of whom received the 162 mg QW TCZ dose (§ Abstract, Methods). The pervasive use of the 162 mg QW starting dose is further acknowledged by the instant specification, which discloses that between October 2013 through June 2016 (Pg. 21, line 28) nearly half of all patients included in the Truven or Optum market surveys started at the “escalated” SC dose of 162 mg QW (42% or 49%, according to Truven or Optum, respectively; Pg. 29, top ¶; Table 3).
Accordingly, the prior art teaches that treatment of RA at a starting dose of 8 mg/kg IV or 162mg QW SC tocilizumab was commonplace in all eligible patients (i.e. 18 years and older) regardless of disposition with respect to age subgroup or anemia status.
Regarding the limitation that the patients treated do not have anemia as rejected under each Emery et al. and Jone et al., Applicant argues that Emery “does not exclude all subjects with anemia” and Jones “has not been shown to exclude subjects with anemia”. However, anticipation of the instant claims does not require that the method taught by the prior art is exclusive to patients without anemia, and each of the studies reported by Emery and Jones expressly report that patients without anemia were treated according to the disclosed method (see Emery Table 1 and Jones Table 1).
Further, regarding the limitation that the patients treated are aged 18-34 as rejected under each Emery et al., Jones et al., and Burmester et al., Applicant argues that each of the applied references does not teach patients in the age range of 18-34 with “sufficient specificity” to anticipate the instant claims. In response, Applicant is directed to MPEP § 2131.03(II), which states with regard to overlapping ranges that what constitutes “sufficient specificity” is fact dependent and is determined on a case-by-case basis. “The question of “sufficient specificity” is similar to that of “clearly envisaging” a species from a generic teaching.”
In the instant case, the teachings of Emery and the method of the instant claims relate to the same therapeutic and dose (8 mg/kg IV TCZ Q4W starting dose) administered to patient populations sharing a lower age boundary of 18 years old. Similarly, the methods disclosed by Jones and Burmester were performed on a population comprising patients 18 years or older. While each of Emery, Jones, and Burmester are silent on a particular subgroup aged 18-34 years, the studies disclosed therein do not recite any age-based exclusions/restrictions within the 18 year or older population, and one of ordinary skill in the art would be able to “at once envisage” treatment of patients within the 18-34 range as species of the disclosure of each Emery, Jones, and Burmester (See MPEP 2131.02(III)).
Moreover, the instant disclosure fails to demonstrate any criticality of the claimed patient features to the practice of the claimed method. The specification provides no analysis of the patients having started at the higher dose of TCZ, but rather employs historical data consolidated from insurance claims to determine which, if any, patient characteristics correlated with an increased likelihood of dose escalation in those that started at the lower dose. There is no demonstrated correlation between these patient metrics in the success or failure of the dose escalation, nor are there examples of improved outcomes in these patient subpopulations when started at the claimed doses.
The specification further provides several important caveats, stating that “the small sample size means that the study results should be interpreted with caution”, that the data came from insured patients based in the US and therefore “may not be generalizable to all patients with RA, nor other countries”, and that “it was not possible to determine the exact reasoning behind the trends observed”.
Indeed, there were inconsistencies in trends even between the two datasets employed by the instantly disclosed study. For example, while the Truven dataset suggested that patients aged 18-34 and those without anemia had increased odds of dose escalation (Pg. 29, last ¶; Table 4), the Optum dataset instead suggested that female patients and those living in the south had increased odds of dose escalation, and that “other factors were not significant” (Pg. 32, first ¶; Table 4).
Claim Rejections - 35 USC § 102/103
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 43 remains rejected under 35 U.S.C. 102(a)(1) as anticipated by or, in the alternative, under 35 U.S.C. 103 as obvious over Emery et al. 2008 (Annals of the rheumatic diseases, 67(11), 1516-1523.; IDS filed 02/26/2024), herein “Emery”, as applied to Claim 36 above, and as evidence by NCT00106522 (ClinicalTrials.gov ID NCT00106522; of record), and NCT01011959 (ClinicalTrials.gov ID NCT01011959; of record).
The teachings of Emery are summarized above.
Regarding Claim 43, Emery is silent on whether the enrolled patients had previously been treated with sarilumab. However, the NCT00106522 study reviewed in Emery completed in 11/2007, which is prior to public availability of sarilumab (Phase 1 clinical trials for sarilumab, aka REGN88/SAR153191, began enrollment 12/2008; See NCT01011959), and therefore, absent evidence to the contrary, none of the patients enrolled in NCT00106522 would have received sarilumab. Moreover, sarilumab, like tocilizumab, is an anti-IL-6R antibody, and therefore it would have been obvious that patients having taken sarilumab would be excluded from a clinical trial designed to determine the efficacy of tocilizumab in order to avoid unnecessary confounding variables.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive because:
Applicant’s arguments do not relate to the additional limitations introduced in Claim 43, but rather applicant contends that Emery does not anticipate Claim 36 from which Claim 43 depends, and therefore Emery cannot anticipate Claim 43. In response, applicant is referred to the above arguments as they relate to anticipation of Claim 36. Briefly, Emery teaches a method of treating patients without anemia with IV tocilizumab at a starting dose of 8 mg/kg Q4W, thereby satisfying the limitations of Claim 36.
Claim Rejections - 35 USC § 103
Claim 59 remains rejected and Claim 46 is newly rejected under 35 U.S.C. 103 as being unpatentable over Emery et al. 2008 (Annals of the rheumatic diseases, 67(11), 1516-1523.; IDS filed 02/26/2024), herein “Emery”, as applied to Claim 36 above.
The teachings of Emery are summarized above.
Regarding Claims 46 and 59, Emery further teaches that 48% of patients were not receiving steroids at baseline (Table 1) and that steroids included “prednisone or equivalent” (§ Study design, ¶1), but Emery is silent on whether said patients had not received steroids within 90 days of tocilizumab treatment.
However, it would have been obvious that the cohort of patients that were not receiving steroids would have been inclusive of those that had not been administered steroids within 90 days. Moreover, Emery teaches that patients receiving the 8 mg/kg tocilizumab dose exhibited the greatest responses (§ Discussion, ¶2), and it therefore would have been obvious to one of ordinary skill in the art to administer the 8 mg/kg dose regardless of steroid use – including those patients who had not received steroids within 90 days.
Response to Arguments
Applicant's arguments filed 09/10/2025 have been fully considered but they are not persuasive because:
Arguments related to the rejection of Claim 59 as obvious over Emery et al. refer to Applicant’s previous arguments regarding the anticipation rejections over the same reference. Briefly argues that Emery does not exclude corticosteroid use within 90 days of the starting dose nor does Emery provide evidence that any of the patients enrolled “met the 90-day corticosteroid-free condition”.
While it is acknowledged that Emery does not teach a required 90-day corticosteroid-free window, the study disclosed by Emery does not have any exclusion criteria relating to patients who were not receiving corticosteroids. Indeed, as pointed out above, at 48% of patients treated were not on corticosteroids at baseline, and patients were treated with the same TCZ dosing regimen (8 mg/kg Q4W) regardless of corticosteroid status.
Although the skilled artisan would be unable to determine the exact length of time for which any of the patients taught by Emery were not taking corticosteroids, it would have been obvious that those that had not received corticosteroids within 90 days could be treated at 8 mg/kg in view of the superior responses achieved in the 8 mg/kg cohort and the lack of any suggestion that the length of time for which the patients were corticosteroid-free was critical to said responses.
NEW REJECTIONS NECESSITATED BY CLAIM AMENDMENTS
Claim Rejections - 35 USC § 112
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.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claim 80 is rejected for the phrase “at a dose that is lower than a starting dose” recited in item “(A)”. It is unclear if the starting dose referred to here is the same as that established in items (I) or (II) (i.e. 162mg weekly or 8 mg/kg Q4W) or if the phrase is referring to a value lower than any starting dose. This rejection can be overcome by amending the claim to read: “at a dose that is lower than the starting dose”.
Claim Rejections - 35 USC § 103
Claims 76-78 are rejected under 35 U.S.C. 103 as being unpatentable over Pappas et al. 2016 (Rheumatology and Therapy, 3(1), 103-115.; PTO-892).
Pappas teaches a study assessing real-world instances of dose escalation in patients with rheumatoid arthritis (RA) treated with tocilizumab (TCZ) (Abstract).
Pappas teaches that patients were 18 years of age or older (§ CERTAIN Substudy) and had moderate or high RA activity.
Pappas teaches that the recommended starting dose of intravenous (IV) TCZ for the treatment of RA varies around the world, and that the recommended starting dose in Japan and European countries is 8 mg/kg every 4 weeks (Q4W)
Pappas teaches the recommended starting dose for IV TCZ in the United States is 4 mg/kg Q4W, but that “(t)he dose may be increased to 8 mg/kg based on clinical response, at the physician’s discretion”.
Pappas highlights that “(t)he ability to administer TCZ in varying doses allows physicians to tailor TCZ therapy to disease activity” (Abstract - Conclusion).
Pappas teaches that 53.1% of patients included in the study were escalated to the 8 mg/kg dose at or before 3 months (§ Results, TCZ Dosing Patterns), with greater than 70% of all patients having been escalated to the 8 mg/kg dose by 6 months (Fig. 1).
Pappas teaches that prior studies suggest that a higher proportion of patients receiving TCZ 8 mg/kg achieved a response by 6 months, and “the option to adjust TCZ dose based on individual clinical responses may have provided an additional benefit to the patients” (Pg. 110).
Pappas teaches that dose escalation occurring prior to 3 months included any time during said period and “could have occurred very close to the baseline visit or very close to the 3-month visit”.
Pappas is silent on the patients’ anemia status and does not particularly point out the ages of those patients that received an escalated dose prior to three months.
However, it would have been obvious to one of ordinary skill in the art that the discretionary TCZ dose escalation from 4 mg/kg to 8 mg/kg before three months as taught by Pappas could be performed at any time prior to 3 months (including at 2 months, 1 month, or sooner) and could be applied to any patient, including those aged 18-34 and those without anemia.
The skilled artisan would have been motivated by the teachings of Pappas which highlight that existing TCZ dosing guidance provides for physician flexibility and discretion when treating RA with TCZ to tailor the dose to the particular needs of an individual based on an assessment of clinical response.
There would have been a reasonable expectation of success because Pappas teaches that the majority of patients elect to increase from 4 mg/kg to 8 mg/kg at or prior to 3 months, because Pappas teaches that the so-called “escalated” dose is the same as the recommended starting dose in many places outside the United States, and because Pappas teaches “the option to adjust TCZ dose based on individual clinical responses may have provided an additional benefit to the patients”.
Conclusion
No claim is allowed.
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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/BRYAN WILLIAM HECK/ Examiner, Art Unit 1643
/JULIE WU/ Supervisory Patent Examiner, Art Unit 1643