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 .
Response to Amendment
This action is written in response to applicant’s amendments received on 1/20/26.
The rejection of the claims under 35 USC112b is overcome by amendment.
The double patent rejection is overcome by amendment.
Amended claims 212, 216-220, 223-227, 229-235 are under examination herein.
Priority
Application claims priority to 62/994,507 provisional application with an effective filing date of 3/25/20. Claims of the instant application are supported by the provisional application and thus have a priority date of 3/25/20.
Information Disclosure Statement
The IDS filed on 12/9/22, 6/10/24, 1/20/26 have been fully considered except where references have been lined through.
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.
Modified rejection necessitated by amendment. Claims 212, 215-219, 223-231 and 233-235 are rejected under 35 U.S.C. 103 as being unpatentable over Faustman (US20180296658A1) and Faustman 2 (US20130115207A1) and Kühtreiber ("Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations." npj Vaccines 3.1 (2018): 23). While Faustman, Faustman 2 and Kuhreiber shares a common inventor and/or assignee, they were published more than 1 year before the effective filing date of instant application and therefore are valid prior art under 35 U.S.C. 102(a)(1).
Regarding claims 212, 215, 218, and 235, Faustman teaches methods of treating and diagnosing disease using biomarkers for BCG therapy (title and abstract). Faustman teaches that the method can involve treatment of a subject using BCG who has an autoimmune disorder (claim 31).Fuastman teaches the subject can be human ([0003]). Faustman teaches that the autoimmune disorder can be diabetes (claims 18 and 32). Faustman teaches the amount of BCG administered should be effective (therapeutically effective) ([0053]). Faustman teaches that administration of BCG results in lower blood glucose level over the course of 2 or more years ([0063]). Faustman teaches “A result of this conversion is the rapid consumption of glucose in vivo. This beneficial effect of BCG is shown, for instance, in FIGS. 3, 8A, and 8B, which demonstrate the ability of BCG to suppress and stabilize glycated hemoglobin levels in human subjects. Glycated hemoglobin is an indicator of total blood glucose concentration and can be used to detect hyperglycemic subjects"” ([0168]). Fausetman teaches that blood glucose can be monitored (detected) for 8 years post administration (fig 8). Therefore, it is obvious to include a detection step in the therapeutic method in order to assess the efficacy of the treatment. Faustman teaches that the use of BCG can replace the use of insulin to control blood glucose (reducing frequency and quantity, benefit) ([0168]).
Faustman does not teach where the administration of the BCG is to a subject where the subject is less than 40 years of age, or explicitly link the reduction of blood glucose to increased cellular uptake.
Kuhtrieber studies BCG vaccination in diabetics (title). Kuhtrieber teaches BCG treatment lowers blood sugar (abstract). Kuhtrieber teaches that the lower blood sugar level is driven by increased cellular glucose uptake (p5 right column first full paragraph.
Faustman and Kuhrtieber do not teach where the administration of the BCG is to a subject where the subject is less than 40 years of age
Faustman 2 teaches methods for the treatment of autoimmune diseases (title). Faustman 2 teaches that BCG can be administered to patients with diabetes (example 1). Faustman 2 teaches that the subjects with diabetes ranged from 18-50 years (example 1). Faustman 2 teaches the diabetic test subjects were on insulin therapy ([0085]). Faustman 2 teaches diabetic subjects enrolled in the trial had an average disease duration of 15 years (range 7-23 years) and an average age of 33 years old (range 26-47) (26-15=11 years old at age of onset) (Table 3).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat diabetic patients with an age of diabetes onset less than 40 years old as taught by Faustman 2 in the BCG therapy of Faustman resulting in the increased uptake of glucose in the subject as taught by Kuhrieber. One of ordinary skill in the art would be motivated to do so because BCG has been used to treat patients with diabetes under 40 years of age. Kuhreiber teaches that the mechanism via the lowering of blood sugar by BCG is the result of increased glucose uptake. One skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. MPEP 2144.04 states that “selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results”. There would be a reasonable expectation of success as both Faustman, Kuhreiber and Faustman 2 are in the same field of endeavor of treating diabetes with BCG.
Regarding claim 216, Faustman 2 teaches that the subjects had no demonstratable insulin secretion (one or more symptoms of diabetes) ([0085]).
Regarding claim 217, Faustman 2 teaches the subject were anti-GAD positive ([0085]).
Regarding claim 219, Faustman teaches the BCG is preferably administered to a subject intradermally, subcutaneously, or intravenously ([0198]).
Regarding claim 223, Faustman teaches the BCG can be administered in multiple doses over years (multiple doses where treatment of not greater than once per year, and not administered during the time elapsed between treatment periods ([0076-0077]).
Regarding claims 224, Faustman teaches that the BCG can be at a range of 5×105 to about 1×107 cfu per 0.1 milligrams of BCG ([0074]). This overlaps the claimed range and therefore the claimed range is prima facia obvious.
Regarding claim 225, Faustman teaches that a second and subsequent doses can be administered 3 years apart ([0077]).
Regarding claim 226, Faustman teaches that the 3rd, 4th, 5th or more doses can be administered 1 year apart (about 12 months) ([0077]).
Regarding claim 227, Faustman teaches that the blood glucose level of a subject before administration of the BCG can be 200 mg/dL or more ([0071]).
Regarding claim 229, Faustman 2 teaches the subjects were undergoing continuous insulin therapy at the time of enrollment into the study (treatment) (example 1, [0085]).
Regarding claim 230, Faustman teaches type 2 diabetes can be treated ([0169]).
Regarding claim 231, Faustman teaches a kit can be created with BCG and instructions ([0057-0060]). Note: MPEP 2141 [R-6] KSR International CO. v. Teleflex Inc. 82 USPQ 2d 1385 (Supreme Court 2007). It is well-settled law that combining printed instructions and an old product into a kit will not render the claimed invention nonobvious even if the instructions detail a new use for the product. See In re Ngai, 367 F.3d 1336, 1339, 70 USPQ2d 1862, 1864 (Fed. Cir. 2004).
Regarding claim 233, Kuhtreiber teaches that the blood sugar can be lowered by 10-18% (Long-term and stable blood sugar reduction with BCG Vaccinations section). This overlaps the claimed range and the claimed range is prima facia obvious.
Regarding claim 234, Fasutman teaches the blood glucose following administration can be 150mg/dl ([0214]).
Claim 220-222 are rejected under 35 U.S.C. 103 as being unpatentable over Faustman (US20180296658A1) and Faustman 2 (US20130115207A1) and Kühtreiber ("Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations." npj Vaccines 3.1 (2018): 23), as applied to 212, 215-219, 223-231 and 233-235 above, and further in view of Cumming ("Relevance of the Warburg effect in tuberculosis for host-directed therapy." Frontiers in cellular and infection microbiology 10 (2018): 576596).
Regarding claim 220, Faustman teaches that the rates of glucose transporters can be determined (glucose uptake) ([0096]). Faustman 2 teaches control subjects can be used as a reference (example 1, [0084]).
Faustman and Faustman 2 do not explicitly teach measuring the glucose uptake of the cells.
Cumming teaches that BCG induces glycolytic flux in cells (abstract). Cummings teaches labeled glucose can be used to monitor cells in real time and non-invasively (p2 second full paragraph and “Extracellular flux analysis” section”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the glucose uptake assay of Cumming in the glucose uptake rate determination of Faustman and the control subjects of Faustman 2. One of ordinary skill in the art would be motivated to do so because Cumming teaches this is a non-invasive and real time assay, and controls are commonly used in the art. Further, one of ordinary skill in the art would be motivated to do so because these assays have been successfully used to monitor glucose uptake and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. There would be a reasonable expectation of success as Faustman, Faustman 2, and Cumming are in the same field of endeavor of studying BCG.
Regarding claim 221, Faustman teaches that the rates of oxidative phosphorylation can be determined ([0096]). Faustman 2 teaches control subjects can be used as a reference (example 1, [0084]).
Faustman and Faustman 2 do not explicitly teach measuring the oxygen consumption rate of the cells.
Cummings teaches that oxygen consumption rate can be monitored non-invasively and in real time in cells to monitor the oxidative phosphorylation rate of the cells (p2 first full paragraph and “Extracellular flux analysis” section”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the oxygen consumption assay of Cumming in the oxidative phosphorylation rate determination of Faustman and the control subjects of Faustman 2. One of ordinary skill in the art would be motivated to do so because Cumming teaches this is a non-invasive and real time assay, and controls are commonly used in the art. Further, one of ordinary skill in the art would be motivated to do so because these assays have been successfully used to monitor oxidative phosphorylation and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. There would be a reasonable expectation of success as Faustman, Faustman 2, and Cumming are in the same field of endeavor of studying BCG.
Regarding claim 222, Faustman teaches that the rates of aerobic glycolysis can be determined ([0096]). Faustman 2 teaches control subjects can be used as a reference (example 1, [0084]).
Faustman and Faustman 2 do not explicitly teach measuring the extra cellular acidification of the cells.
Cumming teaches that BCG induces glycolytic flux in cells (abstract). Cummings teaches that extracellular acidification rate can be monitored non-invasively and in real time in cells to monitor the glycolysis rate of the cells (p2 first full paragraph and “Extracellular flux analysis” section”).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the extra cellular acidification assay of Cumming in the aerobic glycolysis rate determination of Faustman and the control subjects of Faustman 2. One of ordinary skill in the art would be motivated to do so because Cumming teaches this is a non-invasive real time assay, and controls are commonly used in the art. Further, one of ordinary skill in the art would be motivated to do so because these assays have been successfully used to monitor glycolysis and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. There would be a reasonable expectation of success as Faustman, Faustman 2, and Cumming are in the same field of endeavor of studying BCG.
Claim 232 is rejected under 35 U.S.C. 103 as being unpatentable over over Faustman (US20180296658A1) and Faustman 2 (US20130115207A1) Kühtreiber ("Long-term reduction in hyperglycemia in advanced type 1 diabetes: the value of induced aerobic glycolysis with BCG vaccinations." npj Vaccines 3.1 (2018): 23), as applied to 212, 215-219, 223-231 and 233-235 above, and further in view of Czajka ("Hyperglycemia induced damage to mitochondrial respiration in renal mesangial and tubular cells: Implications for diabetic nephropathy." Redox biology 10 (2016): 100-107).
Regarding claim 232, Faustman, Faustman 2, and Kuhtreiber do not explicitly teach the rate of aerobic glycolysis.
Czajka studies the rate of glycolysis in diabetes (abstract). Czajka teaches that the basal glycolysis rate is ~10 mpH units/min measured via ECAR (fig 1). As evidenced by instant specification [0406], ECAR measures aerobic glycolysis. Czajka teaches that the level of glycolysis can be less than 10 when challenged with high glucose (fig 3). Czajka teaches that there is a strong need to understand the molecular mechanisms that lead to kidney damage in diabetes to reduce morbidity and mortality (p103 discussion).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify the use the ECAR readings of Czajka in the method of Kuhtreiber, Faustman and Faustman 2. One of ordinary skill in the art would be motivated to do so because Czajka teaches there is a need to use these readings to reduce morbidity and mortality in diabetes. Further, one of ordinary skill in the art would be motivated to do so because these measurements have been successfully used in diabetes, and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. There would be a reasonable expectation of success as Czajka, Kuhtreiber, Faustman and Faustman 2 are in the same field of endeavor of diabetes.
Response to Arguments
Applicant’s arguments with respect to the claims have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TREVOR L KANE whose telephone number is (571)272-0265. The examiner can normally be reached M-F 7:00 am-4:00pm.
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/TREVOR KANE/Examiner, Art Unit 1657
/ROBERT J YAMASAKI/Primary Examiner, Art Unit 1657
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