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 .
Priority
The instant Application claims priority to U.S. Provisional Applications 63/161,219 and 63/211,439, filed March 15, 2021 and June 16, 2021, respectively. The full age range recited in claims 2, 54, and 100 are not supported by U.S. Provisional Applications 63/161,219 and 63/211,439. In particular, the Provisional Applications do not teach treating a patient as young as 5 years old. PCT/US2022/071133, filed March 14, 2022, first discloses treating an individual as young as 5 years old.
Thus, the instant claims which all depend for claims 2, 54, and 100 are examined with the effective filing date of March 14, 2022.
Should Applicant disagree with the analysis above, he or she may point to the precise locations within U.S. Provisional Applications 63/161,219 and 63/211,439 which disclose treatment of the claimed age range.
Claim Rejections - 35 USC § 102
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 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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 2, 7, 8, 10, 15, 16, 18, 20, 22, 24, 26, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by the Clinical Trial Listing for NCT05039619 (ClinicalTrials.gov; Published: September 1, 2021) as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012).
Regarding claims 2, 54, 94, and 100, the Clinical Trial Listing for NCT05039619 teaches treating children 12-17 years old with obinutuzumab; see Eligibility and Arms and Interventions. Note that the instant claims are drawn to treating “an individual” and does not require treating multiple patients across the scope of ages 5-17 years old.
Obinutuzumab comprises the following heavy and light chain sequences below as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN):
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Regarding claims 2 and 54, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above. Regarding claim 93, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above.
Regarding the limitation “afucosylated” in claims 2 and 54, the International Nonproprietary Names for Pharmaceutical Substances (INN) evidences that obinutuzumab comprises a non-fucosylated residue at position 299 which aligns with N297 by EU numbering.
Regarding the dosing schedule of claims 2, 7, 8, 10, 15, 16, 18, 20, 22, 24, 54, 87, 95, and 100, the Clinical Trial Listing for NCT05039619 teaches three exposures to IV obinutuzumab consisting of a 1000mg dose on days 1 and 14, and week 24, week 26, and week 52 for patients above 45kg body weight. Those below 45kg body weight are administered 20 mg/kg obinutuzumab; see the Arms and Interventions.
Regarding claims 26 and 29, the Clinical Trial Listing for NCT05039619 teaches that the individual may have class III or class IV lupus nephritis with or with class I concomitant disease; see Inclusion Criteria.
Regarding claims 42, 43, and 107, the Clinical Trial Listing for NCT05039619 teaches that patients receiving obinutuzumab will receive mycophenolate mofetil (MMF). Further, regarding claims 109 and 112, the Clinical Trial Listing for NCT05039619 teaches that patients receiving obinutuzumab will also receive oral prednisone and methylprednisolone IV as pre-medication prior to infusions.
Regarding the limitation in claim 54 (“wherein, after administration of the type II anti-CD20 antibody, B cells are depleted to a level […]”), this is an inherent property of the recited method. The method requires only one step – administering the type II anti-CD20 antibody comprising instant SEQ ID NOs: 7 and 8 and which is afucosylated. The depletion of B cells as recited in the final wherein clause of claim 54 flows from the step of administering the recited antibody.
Thus, claims 2, 7, 8, 10, 15, 16, 18, 20, 22, 24, 26, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 are anticipated by the Clinical Trial Listing for NCT05039619 (ClinicalTrials.gov; Published: September 1, 2021) as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012).
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 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 are rejected under 35 U.S.C. 103 as being unpatentable over the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021) as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012) in view of Brunetta (WO 2016/183104 A1; Published: November 17, 2016), Brunetta (US 2006/0024295 A1; Published: February 2, 2006), Rovin et al. (Arthritis & Rheumatism. 64(4): 1215-1226; Published: April 2012) and Furie et al. (Arthritis Rheumatology. 71(suppl 10): Abstract 939; Published: November 2019).
Regarding claims 2, 54, 87, 94, and 100, the Clinical Trial Listing for NCT04702256 teaches treating children 14-17 years old with IV obinutuzumab; see Eligibility and Arms and Interventions. Note that the instant claims are drawn to treating “an individual” and does not require treating multiple patients across the scope of ages 5-17 years old.
Obinutuzumab comprises the following heavy and light chain sequences below as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN):
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Regarding claims 2 and 54, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above. Regarding claim 93, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above.
Regarding the limitation “afucosylated” in claims 2 and 54, the International Nonproprietary Names for Pharmaceutical Substances (INN) evidences that obinutuzumab comprises a non-fucosylated residue at position 299 which aligns with N297 by EU numbering.
Regarding claims 26 and 29, the Clinical Trial Listing for NCT04702256 teaches treating patients with class III or class IV disease including with concomitant class V disease; see inclusion criteria.
Regarding claims 42, 43, and 107, the Clinical Trial Listing for NCT04702256 teaches treating patients with a regimen which includes standard of care mycophenolate mofetil; see Arms and Interventions. Regarding claims 109 and 112, the Clinical Trial Listing for NCT04702256 teaches treating the patients with a regimen that further comprises oral prednisone and methylprednisolone as a premedication prior to each administration of obinutuzumab; see Arms and Interventions.
The Clinical Trial Listing for NCT04702256 does not teach the precise dose and dosing schedule recited in claims 2, 7, 8, 10, 15, 16, 18, 20, 22, 24, 54, 87, 95, and 100 nor the use of the regimen in patients with class III (C) or IV (C) disease.
Regarding the dosing schedule of claims 2, 7, 8, 15, 16, 20, 24, 54, 87, 95, and 100, WO 2016/183104 A1 teaches treatment of lupus nephritis (LN) by two exposures of type II anti-CD20 antibody obinutuzumab, where each exposure comprises two 1000mg IV doses, with the first exposure occurring at day 0 and week 2, and the second occurring at week 24 and 26; see Figure 1. The antibody was administered with mycophenolate mofetil (MMF) and the corticosteroid oral prednisone; see paragraph 0235. The total of the one or two antibody doses of each of the first and second exposures is about 1800mg to about 2200 mg, and/or each of the first and second doses is 900-1100mg; see paragraph 0014 and 0199. Regarding the effect of type II anit-CD20 antibody treatment in claim 54, WO 2016/183104 A1 teaches that after administration of obinutuzumab, the B cell depletion in the individual may be about 90% or wherein circulating peripheral B cells are reduced to a level of about 1-10 cells/µL or fewer; see paragraph 0219. Finally, regarding claims 26, 28, and 29, WO 2016/183104 A1 teaches that the individual treated has class III or IV LN, including class III(C) or IV(C) and may also have concomitant class V; see paragraphs 0192-0194.
WO 2016/183104 A1 does not teach a third antibody exposure.
US 2006/0024295 A1 teaches treatment of class III or IV lupus nephritis (LN) with the anti-CD20 antibody rituximab; see Example 1. Patients were administered mycophenolate mofetil (MMF) and corticosteroids in conjunction with intravenous rituximab, which was given as 1000mg at days 1, 15, 168 (i.e. week 24), and 182 (i.e. week 26); see Examples 1 and paragraph 0235. After 52 weeks, subject may receive additional rituximab infusions; see paragraph 0241. A third exposure between 12-18 months after initial therapy in a single 2000mg dose or in two 1000mg doses spread over about 2 weeks is expected to be effective for continuing the response; see paragraph 0242. US 2006/0024295 A1 teaches that this third exposure "would be effective in continuing the response of initial therapy or inducing another complete/partial response if the subject experiences a flare”; see paragraph 0242.
Rovin et al teaches that the days 1, 15, 168, and 182 dosing of rituximab in patients with lupus nephritis resulted in an ORR at 52 weeks of 56.9% and 45.8% in the rituximab and placebo groups, respectively. Rovin et al. demonstrates that the median CD19+ peripheral cell count increases beginning after day 308 following the first rituximab infusion; see Figure 3. Furie et al. evaluated the same dosing schedule of days 1, 15, 168, and 182 of obinutuzumab in lupus nephritis patients with a similar ORR at 52 weeks of 55.6% and 35.5% in the obinutuzumab and placebo groups, respectively. Despite, the two studies demonstrating similar proportions of the anti-CD20 drug-receiving treatment group achieving ORR, the proportion of patients achieving CRR at 52 weeks is greater with obinutuzumab (34.9% vs 22.6% in placebo) than rituximab (26.4% vs. 30.6% for placebo).
Because the 52 week ORR between obinutuzumab and rituximab are similar (55.6% vs 56.9%) and because Rovin et al. teaches that the number of CD19+ peripheral cells increases just before 365 days following the first rituximab infusion, it would have been obvious to modify the dosing regimen of obinutuzumab as taught by WO 2016/183104 A1 to include a third rituximab exposure Day 365 after the first infusion as guided by US 2006/0024295 A1 and the data of Rovin et al. Despite, the two studies demonstrating similar proportions of the anti-CD20 drug-receiving treatment group achieving ORR, the proportion of patients achieving CRR at 52 weeks is greater with obinutuzumab (34.9% vs 22.6% in placebo) than rituximab (26.4% vs. 30.6% for placebo); see Furie et al. and Rovin et al. Because US 2006/0024295 guides for the use of a third exposure dose of rituximab, which demonstrated a lower CRR than obinutuzumab, one would have had a reasonable expectation of success modifying the dosing regimen taught by WO 2016/183104 A1 to include a third exposure taught by US 2006/0024295 A1. Despite WO 2016/183104 A1 exemplifying the dosing regimen in a trial of adult lupus nephritis patients, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success applying the modified dosing regimen taught by WO 2016/183104 A1 and US 2006/0024295 A1 to the 14–17-year-old patient population of the Clinical Trial Listing for NCT04702256 because the Clinical Trial Listing for NCT04702256 teaches treating 14-17 year old patients with obinutuzumab.
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 10, 18, and 22 are rejected under 35 U.S.C. 103 as being unpatentable the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021) as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012) in view of Brunetta (WO 2016/183104 A1; Published: November 17, 2016), Brunetta (US 2006/0024295 A1; Published: February 2, 2006), Rovin et al. (Arthritis & Rheumatism. 64(4): 1215-1226; Published: April 2012) and Furie et al. (Arthritis Rheumatology. 71(suppl 10): Abstract 939; Published: November 2019) as applied to claim(s) 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 above, and further in view of Umana et al. (WO 2005/044859 A2; Published: May 19, 2005).
The teachings of the Clinical Trial Listing for NCT04702256 as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) in view of Brunetta (WO 2016/183104 A1), Brunetta (US 2006/0024295 A1), Rovin et al., and Furie et al. as related to claim(s) 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112, from which these claims depend are given previously in this Office action and are fully incorporated here.
None of the above references teach dosing obinutuzumab at 20mg/kg for patients under 45kg.
Umana et al. teaches type II anti-CD20 antibodies, including one antibody comprising the VH of instant SEQ ID NO: 7 and the VL of instant SEQ ID NO: 8 – the same VH and VL sequences of obinutuzumab. Umana et al. teaches treating lupus nephritis with the type II anti-CD20 antibodies; see paragraph 0176. Umana et al. teaches that the dose and regimen depend on several factors, including the judgement of the treating physician, but generally will range from about 0.01 to 2000 mg/kg; see paragraph 0190. Further, Umana et al. teaches the doses should be titrated to the individual patient; see paragraph 0190. Umana et al. teaches that therapeutically effective doses administered parenterally, which includes IV, range from about 0.1 to 20 mg/kg.
While WO 2016/183104 A1 teaches using a fixed dose of obinutuzumab, the examples are restricted to patients over the age of 18 years old. It would have been obvious to one of ordinary skill in the art to adjusted the dose for a patient with a smaller body weight, especially given the teaching by Umana et al. that doses should be developed for each individual patient. Umana et al. does not teach body weight specific dosing, but does teach that optimization is needed to arrive at the appropriate dose and schedule; see paragraphs 0190-0199. The Clinical Trial Listing for NCT04702256 is the first clinical trial of obinutuzumab in a pediatric lupus setting and, in line with guidance by Umana et al., routine optimization would be required to achieve safe and effective doses for patients having a broad range of body sizes. Indeed, one of ordinary skill would have arrived at the 20mg/kg dose for patients less than 45kg by routine experimentation.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
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 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 114 and 171-198 of copending Application No. 18/814,259 in view of the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021) and as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012).
Regarding instant claims 2, 7, 8, 15, 16, 20, 54, 87, 94, 95, and 100, copending claims 114, 174, 179-187, and 192-195 teach treating lupus nephritis comprising three antibody exposures obinutuzumab, wherein the first two exposures comprise one or two doses about 2 weeks apart at about 1000mg per dose and the third dose is one 1000mg dose.
Obinutuzumab comprises the following heavy and light chain sequences below as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN):
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Regarding claims 2 and 54, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above. Regarding claim 93, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above.
Regarding the limitation “afucosylated” in claims 2 and 54, the International Nonproprietary Names for Pharmaceutical Substances (INN) evidences that obinutuzumab comprises a non-fucosylated residue at position 299 which aligns with N297 by EU numbering.
Regarding, instant claims 26, 28, and 29, copending claims 175-178 and 188-191 teach treating patients with class III, class IV, class III(C), or class IV (C) with concomitant class V disease. Regarding instant claims 42, 43, 107, 109, and 112, copending claims 171-173 and 196-198 teach treating along with standard of care, oral prednisone, MMF, and methylpredinisone.
The copending claims are silent to the age of individual being treated.
The Clinical Trial Listing for NCT04702256 teaches treating children 14-17 years old with IV obinutuzumab; see Eligibility and Arms and Interventions. Note that the instant claims are drawn to treating “an individual” and does not require treating multiple patients across the scope of ages 5-17 years old. Further, the Clinical Trial Listing for NCT04702256 teaches treating patients with class III or class IV disease including with concomitant class V disease, treating patients with a regimen which includes standard of care mycophenolate mofetil, oral prednisone and methylprednisolone as a premedication prior to each administration of obinutuzumab; see inclusion criteria and Arms and Interventions.
Because both the copending claims and the Clinical Trial Listing for NCT04702256 teach treating the same disease and using the same medications, it would have been obvious to one of ordinary skill in the art to apply and one would have had a reasonable expectation of success to use the dose regimen taught by the copending claims on the patient population of Clinical Trial Listing for NCT04702256 which includes patients 14-17 years old.
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.
Claims 10, 18, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 114 and 171-198 of copending Application No. 18/814,259 in view of the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021) and as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012) as applied to claim(s) 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 above, and further in view of Umana et al. (WO 2005/044859 A2; Published: May 19, 2005).
None of the above references teach dosing obinutuzumab at 20mg/kg for patients under 45kg.
Umana et al. teaches type II anti-CD20 antibodies, including one antibody comprising the VH of instant SEQ ID NO: 7 and the VL of instant SEQ ID NO: 8 – the same VH and VL sequences of obinutuzumab. Umana et al. teaches treating lupus nephritis with the type II anti-CD20 antibodies; see paragraph 0176. Umana et al. teaches that the dose and regimen depend on several factors, including the judgement of the treating physician, but generally will range from about 0.01 to 2000 mg/kg; see paragraph 0190. Further, Umana et al. teaches the doses should be titrated to the individual patient; see paragraph 0190. Umana et al. teaches that therapeutically effective doses administered parenterally, which includes IV, range from about 0.1 to 20 mg/kg.
While the copending claims teach using a fixed dose of obinutuzumab, the claims are silent to a patient age or body size. It would have been obvious to one of ordinary skill in the art to adjusted the dose for a patient with a smaller body weight, especially given the teaching by Umana et al. that doses should be developed for each individual patient. Umana et al. does not teach body weight specific dosing, but does teach that optimization is needed to arrive at the appropriate dose and schedule; see paragraphs 0190-0199.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
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.
Claims 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-24, and 29-41 of copending Application No. 19/285,781 in view of the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021), Brunetta (US 2006/0024295 A1; Published: February 2, 2006), Rovin et al. (Arthritis & Rheumatism. 64(4): 1215-1226; Published: April 2012) and Furie et al. (Arthritis Rheumatology. 71(suppl 10): Abstract 939; Published: November 2019) and as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012).
Regarding instant claims 2, 7, 8, 15, 16, 20, 54, 87, 94, 95, and 100, copending claims 1-12, 15, 16, and 34-41 teach treating lupus nephritis comprising two antibody exposures of IV obinutuzumab, wherein each exposure comprises one or two doses about 2 weeks apart at about 1000mg per dose.
Obinutuzumab comprises the following heavy and light chain sequences below as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN):
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Regarding claims 2 and 54, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above. Regarding claim 93, instant SEQ ID NO: 7 is 100% identical to residues 1-119 in the heavy chain sequence above and instant SEQ ID NO: 8 is 100% identical to residues 1-115 in the light chain sequence above.
Regarding the limitation “afucosylated” in claims 2 and 54, the International Nonproprietary Names for Pharmaceutical Substances (INN) evidences that obinutuzumab comprises a non-fucosylated residue at position 299 which aligns with N297 by EU numbering.
Regarding, instant claims 26 and 29, copending claims 13, 15, and 18 teach treating patients with class III or class IV, with concomitant class V disease. Regarding instant claims 42, 43, 107, 109, and 112, copending claims 19-24 and 29-32 teach treating along with standard of care, oral prednisone, MMF, and methylpredinisone.
The copending claims are silent to the age of individual being treated, do not teach treating class III (C) or class IV (C), nor teach a third antibody exposure.
The Clinical Trial Listing for NCT04702256 teaches treating children 14-17 years old with IV obinutuzumab; see Eligibility and Arms and Interventions. Note that the instant claims are drawn to treating “an individual” and does not require treating multiple patients across the scope of ages 5-17 years old. Further, the Clinical Trial Listing for NCT04702256 teaches treating patients with class III or class IV disease including with concomitant class V disease, treating patients with a regimen which includes standard of care mycophenolate mofetil, oral prednisone and methylprednisolone as a premedication prior to each administration of obinutuzumab; see inclusion criteria and Arms and Interventions. The Clinical Trial Listing for NCT04702256 does not teach the precise dose and dosing schedule recited in claims 2, 7, 8, 10, 15, 16, 18, 20, 22, 24, 54, 87, 95, and 100 nor the use of the regimen in patients with class III (C) or IV (C) disease.
Neither the copending claims nor the Clinical Trial Listing for NCT04702256 teach treating class III (C) or class IV (C).
Regarding the dosing schedule of claims 2, 7, 8, 15, 16, 20, 24, 54, 87, 95, and 100, WO 2016/183104 A1 teaches treatment of lupus nephritis (LN) by two exposures of type II anti-CD20 antibody obinutuzumab, where each exposure comprises two 1000mg IV doses, with the first exposure occurring at day 0 and week 2, and the second occurring at week 24 and 26; see Figure 1. The antibody was administered with mycophenolate mofetil (MMF) and the corticosteroid oral prednisone; see paragraph 0235. The total of the one or two antibody doses of each of the first and second exposures is about 1800mg to about 2200 mg, and/or each of the first and second doses is 900-1100mg; see paragraph 0014 and 0199. Regarding the effect of type II anit-CD20 antibody treatment in claim 54, WO 2016/183104 A1 teaches that after administration of obinutuzumab, the B cell depletion in the individual may be about 90% or wherein circulating peripheral B cells are reduced to a level of about 1-10 cells/µL or fewer; see paragraph 0219. Finally, regarding claims 26, 28, and 29, WO 2016/183104 A1 teaches that the individual treated has class III or IV LN, including class III(C) or IV(C) and may also have concomitant class V; see paragraphs 0192-0194.
Neither the copending claims, the Clinical Trial Listing for NCT04702256, nor WO 2016/183104 A1 does not teach a third antibody exposure.
US 2006/0024295 A1 teaches treatment of class III or IV lupus nephritis (LN) with the anti-CD20 antibody rituximab; see Example 1. Patients were administered mycophenolate mofetil (MMF) and corticosteroids in conjunction with intravenous rituximab, which was given as 1000mg at days 1, 15, 168 (i.e. week 24), and 182 (i.e. week 26); see Examples 1 and paragraph 0235. After 52 weeks, subject may receive additional rituximab infusions; see paragraph 0241. A third exposure between 12-18 months after initial therapy in a single 2000mg dose or in two 1000mg doses spread over about 2 weeks is expected to be effective for continuing the response; see paragraph 0242. US 2006/0024295 A1 teaches that this third exposure "would be effective in continuing the response of initial therapy or inducing another complete/partial response if the subject experiences a flare”; see paragraph 0242.
Rovin et al teaches that the days 1, 15, 168, and 182 dosing of rituximab in patients with lupus nephritis resulted in an ORR at 52 weeks of 56.9% and 45.8% in the rituximab and placebo groups, respectively. Rovin et al. demonstrates that the median CD19+ peripheral cell count increases beginning after day 308 following the first rituximab infusion; see Figure 3. Furie et al. evaluated the same dosing schedule of days 1, 15, 168, and 182 of obinutuzumab in lupus nephritis patients with a similar ORR at 52 weeks of 55.6% and 35.5% in the obinutuzumab and placebo groups, respectively. Despite, the two studies demonstrating similar proportions of the anti-CD20 drug-receiving treatment group achieving ORR, the proportion of patients achieving CRR at 52 weeks is greater with obinutuzumab (34.9% vs 22.6% in placebo) than rituximab (26.4% vs. 30.6% for placebo).
Because the 52 week ORR between obinutuzumab and rituximab are similar (55.6% vs 56.9%) and because Rovin et al. teaches that the number of CD19+ peripheral cells increases just before 365 days following the first rituximab infusion, it would have been obvious to modify the dosing regimen of obinutuzumab as taught by the copending claims or WO 2016/183104 A1 to include a third rituximab exposure Day 365 after the first infusion as guided by US 2006/0024295 A1 and the data of Rovin et al. Despite, the two studies demonstrating similar proportions of the anti-CD20 drug-receiving treatment group achieving ORR, the proportion of patients achieving CRR at 52 weeks is greater with obinutuzumab (34.9% vs 22.6% in placebo) than rituximab (26.4% vs. 30.6% for placebo); see Furie et al. and Rovin et al. Because US 2006/0024295 guides for the use of a third exposure dose of rituximab, which demonstrated a lower CRR than obinutuzumab, one would have had a reasonable expectation of success modifying the dosing regimen taught by the copending claims or WO 2016/183104 A1 to include a third exposure taught by US 2006/0024295 A1. Despite the copending claims and WO 2016/183104 A1 being silent to the age of the lupus nephritis patients or exemplifying treatment in adults only, it would have been obvious to one of ordinary skill in the art and one would have had a reasonable expectation of success applying the modified dosing regimen taught by the copending claims, WO 2016/183104 A1, and US 2006/0024295 A1 to the 14–17-year-old patient population of the Clinical Trial Listing for NCT04702256 because the Clinical Trial Listing for NCT04702256 teaches treating 14-17 year old patients with obinutuzumab.
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.
Claims 10, 18, and 22 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-13, 15-24, and 29-41 of copending Application No. 19/285,781 in view of the Clinical Trial Listing for NCT04702256 (ClinicalTrials.gov; Published: January 12, 2021), Brunetta (US 2006/0024295 A1; Published: February 2, 2006), Rovin et al. (Arthritis & Rheumatism. 64(4): 1215-1226; Published: April 2012) and Furie et al. (Arthritis Rheumatology. 71(suppl 10): Abstract 939; Published: November 2019) and as evidenced by the International Nonproprietary Names for Pharmaceutical Substances (INN) (WHO Drug Information. 26(4): 401-471; Published: 2012) as applied to claim(s) 2, 7, 8, 15, 16, 20, 24, 26, 28, 29, 42, 43, 54, 87, 93-95, 100, 107, 109, and 112 above, and further in view of Umana et al. (WO 2005/044859 A2; Published: May 19, 2005).
None of the above references teach dosing obinutuzumab at 20mg/kg for patients under 45kg.
Umana et al. teaches type II anti-CD20 antibodies, including one antibody comprising the VH of instant SEQ ID NO: 7 and the VL of instant SEQ ID NO: 8 – the same VH and VL sequences of obinutuzumab. Umana et al. teaches treating lupus nephritis with the type II anti-CD20 antibodies; see paragraph 0176. Umana et al. teaches that the dose and regimen depend on several factors, including the judgement of the treating physician, but generally will range from about 0.01 to 2000 mg/kg; see paragraph 0190. Further, Umana et al. teaches the doses should be titrated to the individual patient; see paragraph 0190. Umana et al. teaches that therapeutically effective doses administered parenterally, which includes IV, range from about 0.1 to 20 mg/kg.
While the copending claims teach using a fixed dose of obinutuzumab, the claims are silent to a patient age or body size. It would have been obvious to one of ordinary skill in the art to adjusted the dose for a patient with a smaller body weight, especially given the teaching by Umana et al. that doses should be developed for each individual patient. Umana et al. does not teach body weight specific dosing, but does teach that optimization is needed to arrive at the appropriate dose and schedule; see paragraphs 0190-0199.
It has long been settled to be no more than routine experimentation for one of ordinary skill in the art to discover an optimum value of a result effective variable. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." Application of Aller, 220 F.2d 454, 456, 105 USPQ 233, 235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." Application of Boesch, 617 F.2d 272, 276, 205 USPQ 215, 218-219 (C.C.P.A. 1980).
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.
Conclusion
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/KATHERINE ANN HOLTZMAN/Examiner, Art Unit 1646
/JULIET C SWITZER/Primary Examiner, Art Unit 1682