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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 8/6/24 has been entered.
Election/Restrictions – Retained for the Record
Applicant's election with traverse of Group I, claims 1-16, 26, 27, in the reply filed on 11/11/22 is acknowledged. The traversal is on the ground(s) that amino acids 107-333 of “the presently claimed methods” is different from amino acids 107-333 in SEQ ID NO:1 of CN102085368B. This is not found persuasive because the sequence applicant references, the entirety of instant SEQ ID NO:1 as currently claimed, was NOT in claim 1 of applicant’s 10/30/20 claim set that was examined for the Restriction Requirement. The 10/30/20 claim 1 was silent on any specific sequence requirement of the Fc portion of the recombinant TACI-Fc fusion protein. That claim 1 was broader than the 11/11/22 claim 1 that has added sequence limitations for the Fc portion (the examiner notes that such limitation still allows for 80% or more sequence identity with amino acids 107-333 of instant SEQ ID NO:1, which is broader than the arguments based on SEQ ID NO:1 unmodified). In any case as to the breadth of what is instantly claimed and how that differs from the previously cited reference, this is not material because the Restriction Requirement was based on examination of the 10/30/20 claim 1 limitations, and CN102085368B was effective in breaking unity of that claim 1.
The requirement is still deemed proper and is therefore made FINAL
Claims 17-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected inventions, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 11/11/22.
Claim Status
Claims 1, 4-11 are pending.
Claims 2, 3, 12-28 are cancelled.
Claims 1, 4-11 are under examination.
Claims 1, 4-11 are rejected.
Priority
The instant application, filed 10/30/2020 and having one RCE-type filing therein is a National Stage entry of PCT/CN2019/128099, International Filing Date: 12/24/2019.
Information Disclosure Statement
The Examiner has considered the reference(s) provided in the 2/17/26 Information Disclosure Statement, and provides a signed and dated copy of such herewith.
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.
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.
Response to Arguments
Applicant's arguments (“Remarks”) filed 2/17/26 have been fully considered but they are not persuasive as set forth below.
Applicant argues that the combination of Fang and the ‘986 application does not teach the instantly claimed SEQ ID NO:1, however the examiner has considered the stated bases for this argument and is not persuaded. The ‘986 sets forth specific bases for modifications found, inter alia, in its SEQ ID NO:33, and making these modifications in the same portion of the Fc found in Fang would have been based on making relevant improvements for reasons described in the ‘986, and such replacement of the same portion would reasonably have resulted in improvements at least for the specific reasons clearly taught in the ‘986. The substitution of the same portion of SEQ ID NO:33 for the Fc portion of Fang’s RC18 sequence results in the same Fc portion as instantly set forth in SEQ ID NO:1. That this does not comprise three differences found in Fang’s ‘replaced’ and improved-by-the-‘986 teachings and sequence portion of its SEQ ID NO:33 does not appear material to the bases for modification. At to the ‘burden of explaining’, this is set forth in the rejection, regarding making modifications specifically directed to particular improvements, see below. The reasons for expecting improvements are clear and self-explanatory, including, from below, “…including to “remove Fcγ1 receptor (FcγRI) and complement (C1q) binding functions,” “Leu-Leu-Gly-Gly; amino acid residues 38 to 41 of SEQ ID NO: 6, which correspond to EU index positions 234 to 237) was mutated to Ala-Glu-Gly-Ala”, and “to introduce a mutation of Ala to Ser (amino acid residue 134 of SEQ ID NO: 6, which corresponds to EU index position 330) and Pro to Ser (amino acid residue 135 of SEQ ID NO: 6, which corresponds to EU index position 331) to reduce complement C1q binding or complement fixation.”” Please also note that SEQ ID NO:33 is explicitly claimed in the ‘986, at claims 9 and 26, further supporting that this sequence would be preferred, or at least of interest for what it provides.
The issue of the additional amino acids at the N-terminus of SEQ ID NO:33 is addressed simply by considering the motivation by one of ordinary skill in the art to replace the portion of Fang’s RC18 that is the Fc portion. This would be the simplest replacement, also there is nothing in the N-terminus portion (which is not added) that was noted of importance for improvement. Applicant’s concerns regarding ‘reverting’ at EU positions 223, 228 and 393 have been considered, however are not considered significant given the ‘986’s SEQ ID NO:33 comprising improvements clearly stated therein and the motivation to substitute this for the Fc portion of Fang to obtain such improvements that would reasonably be expected to result in an overall improvement in performance.
As to arguments against Merrill, regardless of any associations or other bases for inapplicability, Merrill is only applied for the dosages, and one of ordinary skill in the art would reasonably consider and apply dosages known and applied in the art for a similar therapeutic with a similar molecular weight at least for initial dosing/evaluations, to treat for the same type of disease/condition.
The responses set forth above apply to the similar arguments against the combination of the ‘316 patent with the ‘986 patent.
Also, these arguments apply with regard to claim 11, which adds Isenberg 2015.
Claim(s) 1, 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over CN102085368B, Jianmin Fang, published 6/12/2013 (Fang, Chinese copy with machine translation provided), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill).
Claim 1 is directed to a method for treating systematic lupus erythematosus (SLE) comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical preparation of a recombinant TACI-Fc fusion protein in a dose of 80, 160 or 240 mg per administration, wherein the recombinant TACI-Fc fusion protein has the sequence as shown in SEQ ID NO:1, and wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
This claimed administered SEQ ID NO:1 in its entirety is understood to be marked/marketed as Telitacicept, also identified as RC18, see pages 8-9 of the 6/13/23 Remarks.
The transition phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps., see MPEP 2111.03 I.
“Treat” or “treating” is not defined in the specification and is given its ordinary and customary meaning in the art, namely to improve or ameliorate one or more conditions or effects of an illness or disease.
Fang teaches that the TACI fusion protein, Atacicept, has been undergoing clinical trials for diseases such as SLE, rheumatoid arthritis, and lymphoma, and results show that Atacicept has clear biological activity and no obvious side effects, para 9 on page 4 of machine translation. Fang teaches that it “used a unique method of a protein precursor processing enzyme artificial neural network computer software system to find the cause of TACI natural sequence degradation, and then used genetic engineering to construct an optimized TACI-Fc fusion protein,” and that the “research results showed that the optimized TACI-Fc fusion protein has better biological activity, has the effect of inhibiting autoimmune diseases, and has potential therapeutic prospects for autoimmune diseases such as SLE and rheumatoid arthritis,” para 10 on page 4.
Fang then teaches more specifically, “The optimized TACI-Fc fusion protein described in the present invention is preferably formed by the fusion of the 13th to 118th amino acid sequence of TACI and the immunoglobulin IgG1 Fc, that is, sequence 1 in the sequence table, hereinafter referred to as RCT-18,” para 18, page 5. Previous to that Fang also teaches multiple sources and sequences of Fc, para 16 page 5.
Fang teaches in multiple locations in the specification that its and other TACI-Fc fusion proteins are used to treat SLE, paras 9, 10, 22, 23, and also compared its rodent treatment of its TACI-Fc fusion protein to that of Atacicept, para 26 on pages 8-9.
The Fang sequence having the same number of amino acids, 333, compared to instantly claimed SEQ ID NO:1 is as follows:
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The TACI portion, 1-106 of the sequence, is identical to that of instant SEQ ID NO:1 however there are differences in the Fc portion.
The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Also, there is a motivation in the art to improve existing therapeutic products to provide a superior treatment therapeutic agent, and this is based on wanting to obtain improved results for patients as well as economic gain by those who are able to provide an improved product. This is evident, for example, in Fang, paras 26 and 27. This is especially the case for difficult to treat diseases such as SLE.
The ‘986 teaches multiple modifications of the Fc portion of TACI-Fc fusion proteins to improve them, see paras 246-249, including to “remove Fcγ1 receptor (FcγRI) and complement (C1q) binding functions,” “Leu-Leu-Gly-Gly; amino acid residues 38 to 41 of SEQ ID NO: 6, which correspond to EU index positions 234 to 237) was mutated to Ala-Glu-Gly-Ala”, and “to introduce a mutation of Ala to Ser (amino acid residue 134 of SEQ ID NO: 6, which corresponds to EU index position 330) and Pro to Ser (amino acid residue 135 of SEQ ID NO: 6, which corresponds to EU index position 331) to reduce complement C1q binding or complement fixation.” Other modifications were made for Fc5, Fc6 and Fc7, paras 259-263.
One resulting mutated IgG1 Fc fragment comprised the amino acid sequence of SEQ ID NO:33, para 22, and claim 25 depending from claims 17, 21-24.
In view of the stated advantages of modifications that resulted in the development of SEQ ID NO:33, such as those set forth in paras 248 and 249, one of ordinary skill in the art would have been motivated to provide those modifications to the Fc portion of the Fang TACI-Fc fusion protein. At a minimum this would have been reasonably expected to provide for decreased Fcγ1 receptor and complement (C1q) binding, so as to provide for a therapeutic agent less likely to result in undesired side reactions when administered.
Accordingly, it would have been obvious to modify the “RCT-18” TACI-Fc sequence of Fang by substituting the Fc portion of Fang’s “RCT-18” sequence with the corresponding portion of the ‘986 SEQ ID NO:33, this substitution based on utilizing an improved Fc portion that the ‘986 teaches decreases Fcγ1 receptor and complement (C1q) binding, so as to provide for a therapeutic agent less likely to result in undesired side reactions and/or degradation when administered. In that the portion of SEQ ID NO:33 of the ‘986 that corresponds with the Fang Fc sequence also has 100 percent sequence identity with the Fc portion of instant SEQ ID NO:1, this would result in meeting the Fc portion of instant SEQ ID NO:1. There would have been a reasonable expectation of success given the known functions of these modified sites along the Fc amino acid sequence.
Neither Fang nor the ‘986 teach the instantly claimed doses of 80, 160 or 240 mg per administration, nor wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
Merrill teaches results of a Phase IIb study on the efficacy and safety of atacicept in patients with SLE, Title, Objective. From the Results section on page 266, “In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.” This teaches that atacicept was effective at both 75 mg and 150 mg doses to treat SLE in subjects having “high levels of disease activity” (HDA), which per page 267 had initial SLEDAI-2K total score ≥10. Based on this and more particularly on over 50 percent of the subjects of each study arm, more than 70 percent for the 150 mg atacicept dose study arm, having a BILAG 2004 1A or 2B score, and also over 25 percent of each study group having serologically active disease, subjects of this study, as understood by the examiner, clearly included those with “moderate to severe SLE prior to receiving the pharmaceutical preparation.”
Both the more moderate (SLEDIA-2K score 6-9) and the HDA subjects showed improvements with the administration of atacicept, particularly at the 150 mg dose, see pages 271, 274, also see Table 1, page 270, indicating SRI responder rates at week 24, indicating treatment effects based on SRI-4 score reductions at the two doses compared with control, and Figure 1, page 270, showing statistical significance in the HDA population at 150 mg atacicept, and Figure 2, page 271, providing additional positive results for the HDA population including more statistically significant improvements over control. Notwithstanding that Merrill teaches that the primary endpoint was not met – this requiring , at least part of the lack of more substantial differences between treatment doses and placebo may be explained as follows, from page 274, “Similar to the much larger BLISS studies, this trial was conducted on a background of standard care and included some adjustments in the steroid dosage, which protects the safety of the sickest subpopulations, but supports high SRI-4 response rates in the placebo group among patients with moderate disease, a tradeoff that may limit the effect size if there is a ceiling of response rates for targeted treatments in a heterogeneous disease.”
Based on favorable secondary results with atacicept at 24 weeks and given the limitations of the study, and in view of the teachings of Fang and the ‘986 (and also considering that the atacicept Fc sequence is identical with that of the ‘986 SEQ ID NO:33, so has the modifications taught by the ‘986 to be improvements), it would have been obvious to administer the improved-over-atacicept TACI-Fc sequence made obvious by the combination of Fang and the ‘986, per above substituting the ‘986 improved Fc portion for the Fang Fc portion, to subjects having moderate to severe SLE prior to receiving the pharmaceutical preparation, at a dosage of 75 mg, 150 mg and similar doses. The rationale is to substitute one therapeutic agent for another where there is a reasoned basis that the substituted therapeutic agent has improved properties and would therefore provide a superior response in SLE subjects, including those having moderate to severe SLE prior to administering this therapeutic agent. There would have been a reasonable expectation of success given the results of Merrill combined with the rational bases set forth in the ‘986 for improved performance when making modifications to the Fc portion of the TACI-Fc fusion protein. As stated in MPEP 2143.02, “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success,” and “Conclusive proof of efficacy is not required to show a reasonable expectation of success.”
The 150 mg dose, as well as the range established by the 75 and 150 mg doses of Merrill, render obvious the claimed doses of 80, 160 and 240 mg, based both on the 150 mg dose being close to the 160 mg dose of claim 1, and also based on the ranges overlapping - 75-150 overlapping 80-240. See MPEP 2144.05.
Accordingly, considering these teachings and results, claim 1 would have been obvious.
Because Merrill administered its therapeutic agent once weekly, page 267, claims 4 and 5 would have been obvious.
Because Fang teaches administering a lyophilized injection, this interpreted to mean that a lyophilized form of the TACI-Fc fusion protein is made soluble in a liquid prior to actual administration to a subject, paras 128, 132 and 136, claims 6 and 7 would have been obvious.
Because Merrill administered its therapeutic agent by subcutaneous injection, page 267, claims 8 and 9 would have been obvious.1
Because Merrill administered its therapeutic agent for consecutive 24 weeks, page 267, claim 10 would have been obvious.
Claim 11 is rejected are rejected under 35 U.S.C. 103 as being unpatentable over CN102085368B, Jianmin Fang, published 6/12/2013 (Fang, Chinese copy and machine translation previously provided), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided), as applied to claim 1 above, and further in view of Isenberg et al., Ann Rheum Dis 2015;74:2006–2015 (Isen, also supplied by applicant as Exhibit D, cleaner copy previously provided).
The rejection of claim 1 as obvious over Fang in view of the ‘986 and Merrill, is set forth above.
Claim 11 depends from claim 1 and state “wherein the pharmaceutical preparation is administered to the subject in need thereof for consecutive 48 weeks or longer.
Neither Fang, the ‘968, nor Merrill, which conducted its study for 24 weeks, explicitly teach the administering for the duration periods of claim 11, for consecutive 48 weeks or longer.
The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Isen teaches results of a study administering atacicept for prevention of flares in patients with moderate-to-severe SLE, in a 52 week study, Title. Although the 150 mg dose arm was discontinued after two deaths, at the time of discontinuation 62 of 144 patients in this arm had completed 52 weeks of study, page 2008. Data indicates beneficial effects extending beyond 24 weeks through to 52 weeks, both for the intention to treat group, results from Figure 2 of Supplemental Data:
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and for similar data for the potential completer population, Figure 2D:
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866
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Both suggest to one of ordinary skill in the art additional benefit in outcome from administering atacicept beyond 24 weeks to 52 weeks for this secondary endpoint of this study (here showing a larger gap between placebo and 150 mg at 52 weeks vs 24 weeks, indicating continued effect in lowering flares).
Such person of ordinary skill in the art would recognize extending to 52 weeks, or about 52 weeks, likely would also benefit other related results in this patient group who have moderate to severe SLE, with a reasonable expectation of success to improve one or more conditions of one or more subjects in such group. The rationale is to modify treatment period to improve outcome, by extending administration period, based on and supported by the data provided in Isen.
Combined with the teachings of the references applied to claim 1, it would have been obvious to administer the pharmaceutical preparation comprising the claim 1 TACI-Fc fusion protein to a subject in need thereof for consecutive 48 weeks or longer.
Therefore claim 11 would have been obvious.
Claim(s) 1, 4-10 are rejected under 35 U.S.C. 103 as being unpatentable over U.S. Patent No. 8193316, inventors Jianmin Fang and Zheng Liu, issued 6/5/12 (‘316), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided).
Claim 1 is directed to a method for treating systematic lupus erythematosus (SLE) comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical preparation of a recombinant TACI-Fc fusion protein in a dose of 80, 160 or 240 mg per administration, wherein the recombinant TACI-Fc fusion protein has the sequence as shown in SEQ ID NO:1, and wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
This claimed administered SEQ ID NO:1 in its entirety is understood to be marked/marketed as Telitacicept, also identified as RC18, see pages 8-9 of the 6/13/23 Remarks.
The transition phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps., see MPEP 2111.03 I.
“Treat” or “treating” is not defined in the specification and is given its ordinary and customary meaning in the art, namely to improve or ameliorate one or more conditions or effects of an illness or disease.
The ‘316 teaches novel biologically active TACI-Fc fusion proteins that bind to BLyS and/or APRIL and uses thereof, Abstract.
SEQ ID NO:3 of the ‘316, one of four exemplified TACI-Fc fusion proteins specified by “T” assignations, this one being T3, is as follows:
SRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCR
KEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELDKPHTCPLCPAPEL
LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKATPPVLDSDGSFFLYSKLTVDK
SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
When compared with instant SEQ ID NO:1, the TACI portion, 1-106 of the sequence, is identical to that of instant SEQ ID NO:1 however there are seven differences in the Fc portion:
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975
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The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Also, there is a motivation in the art to improve existing therapeutic products to provide a superior treatment therapeutic agent, and this is based on wanting to obtain improved results for patients as well as economic gain by those who are able to provide an improved product that can be marketed with exclusivity for a period of time.
The ‘986 teaches multiple modifications of the Fc portion of TACI-Fc fusion proteins to improve them, see paras 246-249, including to “remove Fcγ1 receptor (FcγRI) and complement (C1q) binding functions,” “Leu-Leu-Gly-Gly; amino acid residues 38 to 41 of SEQ ID NO: 6, which correspond to EU index positions 234 to 237) was mutated to Ala-Glu-Gly-Ala”, and “to introduce a mutation of Ala to Ser (amino acid residue 134 of SEQ ID NO: 6, which corresponds to EU index position 330) and Pro to Ser (amino acid residue 135 of SEQ ID NO: 6, which corresponds to EU index position 331) to reduce complement C1q binding or complement fixation.” Other modifications were made for Fc5, Fc6 and Fc7, paras 259-263.
One resulting mutated IgG1 Fc fragment comprised the amino acid sequence of SEQ ID NO:33, para 22, and claim 25 depending from claims 17, 21-24.
In view of the stated advantages of modifications that resulted in the development of SEQ ID NO:33, such as those set forth in paras 248 and 249, one of ordinary skill in the art would have been motivated to provide those modifications to the Fc portion of the T3 ‘316 TACI-Fc fusion protein. At a minimum this would have been reasonably expected to provide for decreased Fcγ1 receptor and complement (C1q) binding, so as to provide for a therapeutic agent less likely to result in undesired side reactions when administered.
Accordingly, it would have been obvious to modify the T3 TACI-Fc sequence of the ‘316 by substituting the portion of sequence of SEQ ID NO:33 of the ‘986 that corresponds with the T3 Fc sequence in order to decrease Fcγ1 receptor and complement (C1q) binding, this corresponding portion having the above-noted paras 246-249 of the ‘986 modifications so as to provide for a therapeutic agent less likely to result in undesired side reactions and/or degradation when administered. There would have been a reasonable expectation of success given the known functions of these modified sites along the Fc amino acid sequence.
Neither the ‘316 nor the ‘986 teach the instantly claimed doses of 80, 160 or 240 mg per administration, nor wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
Merrill teaches results of a Phase IIb study on the efficacy and safety of atacicept, a TACI-Fc fusion therapeutic protein having similar sequence and molecular weight with other TACI-Fc proteins, in patients with SLE, Title, Objective. From the Results section on page 266, “In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.” This teaches that atacicept was effective at both 75 mg and 150 mg doses to treat SLE in subjects having “high levels of disease activity” (HDA), which per page 267 had initial SLEDAI-2K total score ≥10. Based on this and more particularly on over 50 percent of the subjects of each study arm, more than 70 percent for the 150 mg atacicept dose study arm, having a BILAG 2004 1A or 2B score, and also over 25 percent of each study group having serologically active disease, subjects of this study, as understood by the examiner, clearly included those with “moderate to severe SLE prior to receiving the pharmaceutical preparation.”
Both the more moderate (SLEDIA-2K score 6-9) and the HDA subjects showed improvements with the administration of atacicept, particularly at the 150 mg dose, see pages 271, 274, also see Table 1, page 270, indicating SRI responder rates at week 24, indicating treatment effects based on SRI-4 score reductions at the two doses compared with control, and Figure 1, page 270, showing statistical significance in the HDA population at 150 mg atacicept, and Figure 2, page 271, providing additional positive results for the HDA population including more statistically significant improvements over control. Notwithstanding that Merrill teaches that the primary endpoint was not met – this requiring , at least part of the lack of more substantial differences between treatment doses and placebo may be explained as follows, from page 274, “Similar to the much larger BLISS studies, this trial was conducted on a background of standard care and included some adjustments in the steroid dosage, which protects the safety of the sickest subpopulations, but supports high SRI-4 response rates in the placebo group among patients with moderate disease, a tradeoff that may limit the effect size if there is a ceiling of response rates for targeted treatments in a heterogeneous disease.”
Based on favorable secondary results with atacicept at 24 weeks and given the limitations of the study, and in view of the teachings of ‘316 and the ‘986 (and also considering that the atacicept Fc sequence is identical with that of the ‘986 SEQ ID NO:33, so has the modifications taught by the ‘986 to be improvements), it would have been obvious to administer the improved-over-atacicept TACI-Fc sequence made obvious by the combination of the ‘316 and the ‘986 to subjects having moderate to severe SLE prior to receiving the pharmaceutical preparation, at dosages of 75 mg, 150 mg and similar doses. The rationale is to substitute one therapeutic agent for another where there is a reasoned basis that the substituted therapeutic agent has improved properties and would therefore provide a superior response in SLE subjects, including those having moderate to severe SLE prior to administering this therapeutic agent. There would have been a reasonable expectation of success given the results of Merrill combined with the rational bases set forth in the ‘986 for improved performance when making modifications to the Fc portion of the TACI-Fc fusion protein. As stated in MPEP 2143.02, “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success,” and “Conclusive proof of efficacy is not required to show a reasonable expectation of success.”
The 150 mg dose, as well as the range established by the 75 and 150 mg doses of Merrill, render obvious the claimed doses of 80, 160 and 240 mg, based both on the 150 mg dose being close to the 160 mg dose of claim 1, and also based on the ranges overlapping - 75-150 overlapping 80-240. See MPEP 2144.05.
Accordingly, considering these teachings and results, claim 1 would have been obvious.
Because Merrill administered its therapeutic agent once weekly, page 267, claims 4 and 5 would have been obvious.
Because the ‘316 teaches administering a lyophilized injection, para 117, this interpreted to mean that a lyophilized form of the TACI-Fc fusion protein is made soluble in a liquid prior to actual administration to a subject, claims 6 and 7 would have been obvious.
Because Merrill administered its therapeutic agent by subcutaneous injection, page 267, claims 8 and 9 would have been obvious.
Because Merrill administered its therapeutic agent for consecutive 24 weeks, page 267, claim 10 would have been obvious.
Claim 11 is rejected are rejected under 35 U.S.C. 103 as being unpatentable over US 8193316, inventors Jianmin Fang and Zheng Liu, issued 6/5/12 (‘316), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill), as applied to claim 1 above, and further in view of Isenberg et al., Ann Rheum Dis 2015;74:2006–2015 (Isen, also supplied by applicant as Exhibit D, cleaner copy provided herein).
The rejection of claim 1 as obvious over the ‘316 in view of the ‘986 and Merrill, is set forth above.
Claim 11 depends from claim 1 and state “wherein the pharmaceutical preparation is administered to the subject in need thereof for consecutive 48 weeks or longer.
Neither the ‘316, the ‘968, nor Merrill, which conducted its study for 24 weeks, explicitly teach the administering for the duration periods of claim 11, for consecutive 48 weeks or longer.
The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Isen teaches results of a study administering atacicept for prevention of flares in patients with moderate-to-severe SLE, in a 52 week study, Title. Although the 150 mg dose arm was discontinued after two deaths, at the time of discontinuation 62 of 144 patients in this arm had completed 52 weeks of study, page 2008. Data indicates beneficial effects extending beyond 24 weeks through to 52 weeks, both for the intention to treat group, results from Figure 2 of Supplemental Data:
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371
653
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and for similar data for the potential completer population, Figure 2D:
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866
1419
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Both suggest to one of ordinary skill in the art additional benefit in outcome from administering atacicept beyond 24 weeks to 52 weeks for this secondary endpoint of this study (here showing a larger gap between placebo and 150 mg at 52 weeks vs 24 weeks, indicating continued effect in lowering flares).
Such person of ordinary skill in the art would recognize extending to 52 weeks, or about 52 weeks, likely would also benefit other related results in this patient group who have moderate to severe SLE, with a reasonable expectation of success to improve one or more conditions of one or more subjects in such group. The rationale is to modify treatment period to improve outcome, by extending administration period, based on and supported by the data provided in Isen.
Combined with the teachings of the references applied to claim 1, it would have been obvious to administer the pharmaceutical preparation comprising the claim 1 TACI-Fc fusion protein to a subject in need thereof for consecutive 48 weeks or longer.
Therefore claim 11 would have been obvious.
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.
Claim(s) 1, 4-10 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 8193316, inventors Jianmin Fang and Zheng Liu, issued 6/5/12 (‘316), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided).
Claim 1 is directed to a method for treating systematic lupus erythematosus (SLE) comprising administering to a subject in need thereof a therapeutically effective amount of a pharmaceutical preparation of a recombinant TACI-Fc fusion protein in a dose of 80, 160 or 240 mg per administration, wherein the recombinant TACI-Fc fusion protein has the sequence as shown in SEQ ID NO:1, and wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
This claimed administered SEQ ID NO:1 in its entirety is understood to be marked/marketed as Telitacicept, also identified as RC18, see pages 8-9 of the 6/13/23 Remarks.
The transition phrase “comprising” is inclusive or open-ended and does not exclude additional, unrecited elements or method steps., see MPEP 2111.03 I.
“Treat” or “treating” is not defined in the specification and is given its ordinary and customary meaning in the art, namely to improve or ameliorate one or more conditions or effects of an illness or disease.
The ‘316 claim 1 is directed to a TACI-Fc fusion protein that comprises a TACI polypeptide that consists of amino acids 13 to 119 of SEQ ID NO:1, or a fragment thereof, that starts at any of amino acids 13 to 29 of SEQ ID NO:1, extends through, and terminates at, any of amino acids 105 to 119 of SEQ ID NO:1 and which binds to BLyS or APRIL or both, or a variant of said polypeptide or fragment thereof that has at least 90% sequence identity with said polypeptide or fragment and which binds to BLyS or APRIL or both; and wherein said fusion protein further comprises an Fc domain, and its claim 10 depends from claim 1, stating “wherein the amino acid sequence of said TACI-Fc fusion protein is selected from the group consisting of SEQ ID NO:2, SEQ ID NO:3, and SEQ ID NO:4.
SEQ ID NO:3 of the ‘316, one of four exemplified TACI-Fc fusion proteins of claim 10, is as follows:
SRVDQEERFPQGLWTGVAMRSCPEEQYWDPLLGTCMSCKTICNHQSQRTCAAFCRSLSCR
KEQGKFYDHLLRDCISCASICGQHPKQCAYFCENKLRSPVNLPPELDKPHTCPLCPAPEL
LGGPSVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVKFNWYVDGVEVHNAKTKPREE
QYNSTYRVVSVLTVLHQDWLNGKEYKCKVSNKALPAPIEKTISKAKGQPREPQVYTLPPS
RDELTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKATPPVLDSDGSFFLYSKLTVDK
SRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK.
When compared with instant SEQ ID NO:1, the TACI portion, 1-106 of the sequence, is identical to that of instant SEQ ID NO:1 however there are seven differences in the Fc portion:
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The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Also, in Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 (Fed. Cir. 2010), the Court determined that claims of a later patent were held invalid for obviousness-type double patenting when the earlier patent claimed a compound and disclosed its utility in its specification, and later patent claimed a method of using the compound for a use described in the specification of the earlier patent. In the ‘316 specification at least paras 5, 31 and 32 disclose the utility of using the claimed compounds to treat or ameliorate pathological immune conditions such as lymphoproliferative disorders, and autoimmune diseases, these including systemic lupus erythematosus (SLE).
Also, there is a motivation in the art to improve existing therapeutic products to provide a superior treatment therapeutic agent, and this is based on wanting to obtain improved results for patients as well as economic gain by those who are able to provide an improved product that can be marketed with exclusivity for a period of time.
The ‘986 teaches multiple modifications of the Fc portion of TACI-Fc fusion proteins to improve them, see paras 246-249, including to “remove Fcγ1 receptor (FcγRI) and complement (C1q) binding functions,” “Leu-Leu-Gly-Gly; amino acid residues 38 to 41 of SEQ ID NO: 6, which correspond to EU index positions 234 to 237) was mutated to Ala-Glu-Gly-Ala”, and “to introduce a mutation of Ala to Ser (amino acid residue 134 of SEQ ID NO: 6, which corresponds to EU index position 330) and Pro to Ser (amino acid residue 135 of SEQ ID NO: 6, which corresponds to EU index position 331) to reduce complement C1q binding or complement fixation.” Other modifications were made for Fc5, Fc6 and Fc7, paras 259-263.
One resulting mutated IgG1 Fc fragment comprised the amino acid sequence of SEQ ID NO:33, para 22, and claim 25 depending from claims 17, 21-24.
In view of the stated advantages of modifications that resulted in the development of SEQ ID NO:33, such as those set forth in paras 248 and 249, one of ordinary skill in the art would have been motivated to substitute those modifications into the Fc portion of the T3 ‘316 TACI-Fc fusion protein. At a minimum this would have been reasonably expected to provide for decreased Fcγ1 receptor and complement (C1q) binding, so as to provide for a therapeutic agent less likely to result in undesired side reactions when administered.
Accordingly, one of ordinary skill in the art would have been motivated to modify the T3 TACI-Fc sequence of the ‘316 by substituting a portion of the sequence of SEQ ID NO:33 of the ‘986 that corresponds with the T3 Fc sequence, and that comprises the noted advantageous modifications therein, in order to decrease Fcγ1 receptor and complement (C1q) binding, so as to provide for a therapeutic agent less likely to result in undesired side reactions and/or degradation when administered. In that the portion of SEQ ID NO:33 of the ‘986 that corresponds with the T3 Fc sequence also has 100 percent sequence identity with the Fc portion of instant SEQ ID NO:1, this would result in meeting the Fc portion of instant SEQ ID NO:1. There would have been a reasonable expectation of success given the known functions of these modified sites along the Fc amino acid sequence.
Neither the ‘316 nor the ‘986 teach the instantly claimed doses of 80, 160 or 240 mg per administration, nor wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
Merrill teaches results of a Phase IIb study on the efficacy and safety of atacicept, a TACI-Fc fusion therapeutic protein having similar sequence and molecular weight with other TACI-Fc proteins, in patients with SLE, Title, Objective. From the Results section on page 266, “In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.” This teaches that atacicept was effective at both 75 mg and 150 mg doses to treat SLE in subjects having “high levels of disease activity” (HDA), which per page 267 had initial SLEDAI-2K total score ≥10. Based on this and more particularly on over 50 percent of the subjects of each study arm, more than 70 percent for the 150 mg atacicept dose study arm, having a BILAG 2004 1A or 2B score, and also over 25 percent of each study group having serologically active disease, subjects of this study, as understood by the examiner, clearly included those with “moderate to severe SLE prior to receiving the pharmaceutical preparation.”
Both the more moderate (SLEDIA-2K score 6-9) and the HDA subjects showed improvements with the administration of atacicept, particularly at the 150 mg dose, see pages 271, 274, also see Table 1, page 270, indicating SRI responder rates at week 24, indicating treatment effects based on SRI-4 score reductions at the two doses compared with control, and Figure 1, page 270, showing statistical significance in the HAD population at 150 mg atacicept, and Figure 2, page 271, providing additional positive results for the HAD population including more statistically significant improvements over control. Notwithstanding that Merrill teaches that the primary endpoint was not met – this requiring , at least part of the lack of more substantial differences between treatment doses and placebo may be explained as follows, from page 274, “Similar to the much larger BLISS studies, this trial was conducted on a background of standard care and included some adjustments in the steroid dosage, which protects the safety of the sickest subpopulations, but supports high SRI-4 response rates in the placebo group among patients with moderate disease, a tradeoff that may limit the effect size if there is a ceiling of response rates for targeted treatments in a heterogeneous disease.”
Based on favorable secondary results with atacicept at 24 weeks and given the limitations of the study, and in view of the teachings of ‘316 and the ‘986, (and also considering that the atacicept Fc sequence is identical with that of the ‘986 SEQ ID NO:33, so has the modifications taught by the ‘986 to be improvements), it would have been obvious to administer the improved-over-atacicept TACI-Fc sequence made obvious by the combination of the ‘316 and the ‘986 to subjects having moderate to severe SLE prior to receiving the pharmaceutical preparation, at dosages of 75 mg, 150 mg and similar doses. The rationale is to substitute one therapeutic agent for another where there is a reasoned basis that the substituted therapeutic agent has improved properties and would therefore provide a superior response in SLE subjects, including those having moderate to severe SLE prior to administering this therapeutic agent. There would have been a reasonable expectation of success given the results of Merrill combined with the rational bases set forth in the ‘986 for improved performance when making modifications to the Fc portion of the TACI-Fc fusion protein. As stated in MPEP 2143.02, “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success,” and “Conclusive proof of efficacy is not required to show a reasonable expectation of success.”
The 150 mg dose, as well as the range established by the 75 and 150 mg doses of Merrill, render obvious the claimed doses of 80, 160 and 240 mg, based both on the 150 mg dose being close to the 160 mg dose of claim 1, and also based on the ranges overlapping - 75-150 overlapping 80-240. See MPEP 2144.05.
Accordingly, considering these teachings and results, claim 1 is rejected under this section.
Because Merrill administered its therapeutic agent once weekly, page 267, claims 4 and 5 are rejected under this section.
Because the ‘316 teaches administering a lyophilized injection, para 117, this interpreted to mean that a lyophilized form of the TACI-Fc fusion protein is made soluble in a liquid prior to actual administration to a subject, claims 6 and 7 are rejected under this section.
Because Merrill administered its therapeutic agent by subcutaneous injection, page 267, claims 8 and 9 are rejected under this section.
Because Merrill administered its therapeutic agent for consecutive 24 weeks, page 267, claim 10 is rejected under this section.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 10 of U.S. Patent No. 8193316, inventors Jianmin Fang and Zheng Liu, issued 6/5/12 (‘316), in view of US 2003/0103986, published 6/5/2003 (‘986), and Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided), as applied to claim 1 above, and further in view of Isenberg et al., Ann Rheum Dis 2015;74:2006–2015 (Isen, also supplied by applicant as Exhibit D, cleaner copy previously provided).
The rejection of claim 1 over the ‘316 in view of the ‘986 and Merrill, is set forth above.
Claim 11 depends from claim 1 and state “wherein the pharmaceutical preparation is administered to the subject in need thereof for consecutive 48 weeks or longer.
Neither the ‘316, the ‘968, nor Merrill, which conducted its study for 24 weeks, explicitly teach the administering for the duration periods of claim 11, for consecutive 48 weeks or longer.
The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Isen teaches results of a study administering atacicept for prevention of flares in patients with moderate-to-severe SLE, in a 52 week study, Title. Although the 150 mg dose arm was discontinued after two deaths, at the time of discontinuation 62 of 144 patients in this arm had completed 52 weeks of study, page 2008. Data indicates beneficial effects extending beyond 24 weeks through to 52 weeks, both for the intention to treat group, results from Figure 2 of Supplemental Data:
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and for similar data for the potential completer population, Figure 2D:
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Both suggest to one of ordinary skill in the art additional benefit in outcome from administering atacicept beyond 24 weeks to 52 weeks for this secondary endpoint of this study (here showing a larger gap between placebo and 150 mg at 52 weeks vs 24 weeks, indicating continued effect in lowering flares).
Such person of ordinary skill in the art would recognize extending to 52 weeks, or about 52 weeks, likely would also benefit other related results in this patient group who have moderate to severe SLE, with a reasonable expectation of success to improve one or more conditions of one or more subjects in such group. The rationale is to modify treatment period to improve outcome, by extending administration period, based on and supported by the data provided in Isen.
Combined with the teachings of the references applied to claim 1, one of ordinary skill in the art would have been motivated to administer the pharmaceutical preparation comprising the claim 1 TACI-Fc fusion protein to a subject in need thereof for consecutive 48 weeks or longer.
Therefore claim 11 is rejected under this section.
Claims 1 and 4-10 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 13 and 18 of copending Application No. 19411823 (reference application) in view of Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided).
Reference application claims 1 a formulation comprising a TACI-FC fusion protein, 5 claim narrows this to the same peptide as instant claim 1, SEQ ID NO:1, and reference application claim 18 is directed to a method that includes administering the claim 1 formulation (which per claim 5 would include the same peptides as instant SEQ ID NO:1) to treat SLE.
However, the reference application does not teach the instantly claimed doses of 80, 160 or 240 mg per administration, nor wherein the subject has moderate to severe SLE prior to receiving the pharmaceutical preparation.
Merrill teaches results of a Phase IIb study on the efficacy and safety of atacicept, a TACI-Fc fusion therapeutic protein having similar sequence and molecular weight with other TACI-Fc proteins, in patients with SLE, Title, Objective. From the Results section on page 266, “In a prespecified sensitivity analysis using study day 1 as baseline, a significantly larger proportion of patients receiving atacicept 75 mg and 150 mg achieved an SRI-4 response at week 24 compared with placebo. In predefined subpopulations with high levels of disease activity (HDA) at baseline, serologically active disease, or both, statistically significant improvements in the SRI-4 and SRI-6 response rates were seen with atacicept versus placebo. A severe risk of disease flare was reduced with atacicept therapy in both the ITT and the HDA populations. The risks of serious adverse events and serious or severe infection were not increased with atacicept as compared with placebo.” This teaches that atacicept was effective at both 75 mg and 150 mg doses to treat SLE in subjects having “high levels of disease activity” (HDA), which per page 267 had initial SLEDAI-2K total score ≥10. Based on this and more particularly on over 50 percent of the subjects of each study arm, more than 70 percent for the 150 mg atacicept dose study arm, having a BILAG 2004 1A or 2B score, and also over 25 percent of each study group having serologically active disease, subjects of this study, as understood by the examiner, clearly included those with “moderate to severe SLE prior to receiving the pharmaceutical preparation.”
Both the more moderate (SLEDIA-2K score 6-9) and the HDA subjects showed improvements with the administration of atacicept, particularly at the 150 mg dose, see pages 271, 274, also see Table 1, page 270, indicating SRI responder rates at week 24, indicating treatment effects based on SRI-4 score reductions at the two doses compared with control, and Figure 1, page 270, showing statistical significance in the HAD population at 150 mg atacicept, and Figure 2, page 271, providing additional positive results for the HAD population including more statistically significant improvements over control. Notwithstanding that Merrill teaches that the primary endpoint was not met – this requiring , at least part of the lack of more substantial differences between treatment doses and placebo may be explained as follows, from page 274, “Similar to the much larger BLISS studies, this trial was conducted on a background of standard care and included some adjustments in the steroid dosage, which protects the safety of the sickest subpopulations, but supports high SRI-4 response rates in the placebo group among patients with moderate disease, a tradeoff that may limit the effect size if there is a ceiling of response rates for targeted treatments in a heterogeneous disease.”
Based on favorable secondary results with atacicept at 24 weeks and given the limitations of the study, and in view of the teachings of ‘316 and the ‘986, (and also considering that the atacicept Fc sequence is identical with that of the ‘986 SEQ ID NO:33, so has the modifications taught by the ‘986 to be improvements), it would have been obvious to administer the improved-over-atacicept TACI-Fc sequence made obvious by the combination of the ‘316 and the ‘986 to subjects having moderate to severe SLE prior to receiving the pharmaceutical preparation, at dosages of 75 mg, 150 mg and similar doses. The rationale is to substitute one therapeutic agent for another where there is a reasoned basis that the substituted therapeutic agent has improved properties and would therefore provide a superior response in SLE subjects, including those having moderate to severe SLE prior to administering this therapeutic agent. There would have been a reasonable expectation of success given the results of Merrill combined with the rational bases set forth in the ‘986 for improved performance when making modifications to the Fc portion of the TACI-Fc fusion protein. As stated in MPEP 2143.02, “Where there is a reason to modify or combine the prior art to achieve the claimed invention, the claims may be rejected as prima facie obvious provided there is also a reasonable expectation of success,” and “Conclusive proof of efficacy is not required to show a reasonable expectation of success.”
The 150 mg dose, as well as the range established by the 75 and 150 mg doses of Merrill, render obvious the claimed doses of 80, 160 and 240 mg, based both on the 150 mg dose being close to the 160 mg dose of claim 1, and also based on the ranges overlapping - 75-150 overlapping 80-240. See MPEP 2144.05.
Accordingly, considering these teachings and results, claim 1 is rejected under this section.
Because Merrill administered its therapeutic agent once weekly, page 267, claims 4 and 5 are rejected under this section.
Because reference application claim 13 teaches a lyophilized formulation, claims 6 and 7 are rejected under this section.
Because Merrill administered its therapeutic agent by subcutaneous injection, page 267, claims 8 and 9 are rejected under this section.
Because Merrill administered its therapeutic agent for consecutive 24 weeks, page 267, claim 10 is rejected under this section.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claim 11 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 5, 13 and 18 of copending Application No. 19411823 (reference application) in view of Merrill et al., ARTHRITIS & RHEUMATOLOGY Vol. 70, No. 2, February 2018, pp 266–276 (Merrill, previously provided), as applied to claim 1 above, and further in view of Isenberg et al., Ann Rheum Dis 2015;74:2006–2015 (Isen, also supplied by applicant as Exhibit D, cleaner copy previously provided).
The rejection of claim 1 is set forth above.
Claim 11 depends from claim 1 and state “wherein the pharmaceutical preparation is administered to the subject in need thereof for consecutive 48 weeks or longer.
Although Merrill conducted its study for 24 weeks, neither the reference application claimed nor Merrill explicitly teaches the administering for the duration periods of claim 11, for consecutive 48 weeks or longer.
The level of skill in the art is moderately high, including at least a B.S. degree in biological, chemical or pharmaceutical sciences, and 2-4 years of experience in the field of treating or researching SLE.
Isen teaches results of a study administering atacicept for prevention of flares in patients with moderate-to-severe SLE, in a 52 week study, Title. Although the 150 mg dose arm was discontinued after two deaths, at the time of discontinuation 62 of 144 patients in this arm had completed 52 weeks of study, page 2008. Data indicates beneficial effects extending beyond 24 weeks through to 52 weeks, both for the intention to treat group, results from Figure 2 of Supplemental Data:
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371
653
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and for similar data for the potential completer population, Figure 2D:
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866
1419
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Both suggest to one of ordinary skill in the art additional benefit in outcome from administering atacicept beyond 24 weeks to 52 weeks for this secondary endpoint of this study (here showing a larger gap between placebo and 150 mg at 52 weeks vs 24 weeks, indicating continued effect in lowering flares).
Such person of ordinary skill in the art would recognize extending to 52 weeks, or about 52 weeks, likely would also benefit other related results in this patient group who have moderate to severe SLE, with a reasonable expectation of success to improve one or more conditions of one or more subjects in such group. The rationale is to modify treatment period to improve outcome, by extending administration period, based on and supported by the data provided in Isen.
Combined with the teachings of the references applied to claim 1, one of ordinary skill in the art would have been motivated to administer the pharmaceutical preparation comprising the claim 1 TACI-Fc fusion protein to a subject in need thereof for consecutive 48 weeks or longer.
Therefore claim 11 is rejected under this section.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOSEPH FISCHER whose telephone number is (571)270-7925. The examiner can normally be reached on Monday to Friday, 9:00 AM to 5:00 PM, however noting that the examiner will not normally be working on Wednesday-Friday and on Monday/Tuesday on alternating weeks, but will promptly answer messages upon his return to work.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 Please also note that the ‘968 teaches subcutaneous administration.
Prosecution Insights