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 .
Election/Restrictions
1. The Election filed July 8, 2026 in response to the Office Action of May 8, 2026 is acknowledged. Applicant elected with traverse Group I and without traverse the species of the biologic drug of infliximab, the choice of administering a different biologic drug if infliximab treatment is discontinued. Also, Applicant chose the species of claim 51(c) but examiner has decided to rejoin the other species of claim 51.
2. Applicants argue that the restriction between Groups I and II was not proper because (1) the two groups are not independent according to MPEP 802.01; and (2) the groups do not lack unity of invention because the special technical feature does make a contribution over the prior art of Rosario (US2019/0255172 A1 pub. 8/22/2019). Specifically, Applicant asserts that Rosario does not disclose the use of anti-drug antibodies as an analyte as part of the basis for the determination of likelihood of achieving a pre-specified threshold concentration of the biologic drug.
The arguments have been considered and are persuasive. Thus, examiner withdraws the restriction between Group I and II and rejoins Group II- claims 26-27, 29-30, 34-35, and 42 to the claims of Group I.
3. Applicant also elected without traverse the species of Group II consisting of a Metropolis-Hastings algorithm, specific data of a subject’s weight from claim 30, the analytes are quantified using a mobility-shift assay or solid-phase immunoassay of claim 35, and the information is received through electronic medical records of claim 42. However, examiner has elected to rejoin all of the species of Group II and examine the claims as written.
3. Claims 1-5, 8-9, 12-13, 16-17, 20-27, 29-30, 34-35, 42, 48-49, and 51 are pending. Claims 4-5, 12-13, and 23-24 are withdrawn as being drawn to non-elected species. Claims 1-3, 8-9, 16-17, 20-22, 25-27, 29-30, 34-35, 42, 48-49, and 51 are currently under prosecution as drawn to the elected species.
Priority
4. Application claims the benefit and priority of PCT/US2022/033757 filed on 6/16/2022 claiming the benefit and priority of provisional applications 63/211,954 filed 6/17/2021 and 63/313,226 filed on 2/23/2022. The Application is granted the priority of provisional application 63/211,954 and the effective filing date of 6/17/2021.
Claim Objections
5. Claim 26 is objected to because of the following informalities: line 3 recites “a algorithm” please correct to “an algorithm”. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
6. Claims 1-3, 8-9, 16-17, 20-22, 25-27, 29-30, 34-35, 42, 48-49, and 51 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 is indefinite due to the following phrases:
“Determining a likelihood of achieving” in (b);
“Pre-specified threshold concentration” in (b);
“if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is above 50%” in (c); and
“if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is below 50%” in (d).
The phrase “determining the likelihood of achieving” is unclear because it is not clear what this step of the method is and how to perform it. The metes and boundaries of the claim limitations of what “determining a likelihood of achieving” would encompass and is unclear and indefinite. Examiner suggest possibly using “probability” instead of “likelihood” which is discussed in the specification and has a clear understanding in the art of performing a method step.
The phrase “pre-specified threshold concentration” is unclear because it does not set a clear boundary for what the pre-specified threshold concentration is and thus makes the claim limitation indefinite. Claim 16 discloses a generic range for a biologic agent of 1 mg/L and 10mg/L which would overcome the rejection if applied to claim 1(b).
The phrases in (c) and (d) of “if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is [above/below] 50%” is unclear because there is no reference for what the threshold concentration would be 50% of. If the limitation of claim 16 was amended as described above, this would overcome the rejection.
For the sake of compact prosecution, examiner will interpret any determination of the analytes discussed in (a)(ii) as meeting a pre-determined value to make a predictive response regarding the treatment response as being drawn to “determining a likelihood of achieving a pre-specified threshold concentration” and whether the pre-specified threshold concentration is above or below 50%.
7. Claims 35 and 42 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 35 and 42 are indefinite because it is unclear how the limitations recited in both claims relate to the depending claim 34. Claim 34 recites “wherein the determining the likelihood of achieving the pre-specified threshold concentration of the biologic drug in the subject is…” referencing step (b) of claim 1 and claim 35 and 42 cite the following limitations:
35(a) the biological sample comprises a serum sample;
35(b) the likelihood that high is equal to or about 90%;
35(c) the analytes quantified in (a)(ii) further comprise a level of C-Reactive Protein (CRP);
35(d) the analytes quantified in (a)(ii) further comprise interleukin 6 (IL-6);
35(e) the analytes quantified in (a)(ii) are quantified with an assay comprising a mobility shift assay or a solid-phase immunoassay; or
35(f) further comprising receiving information about the subject, wherein the information comprises a severity of the immune-mediated inflammatory disease or a symptom thereof;
42(a) the severity of the immune-mediated inflammatory disease comprises a disease remission, a disease recurrence, a disease type, or any combination thereof;
42(b) the severity of the symptom of the immune-mediated inflammatory disease comprises a frequency of the symptom, a type of the symptom, or a combination thereof;
42(c) the severity of the immune-mediated inflammatory disease or symptom thereof is based on a clinical disease activity index (CDAI) score;
42(d) the receiving the information about the subject comprises receiving one or more electronic medical records (EMRs), wherein the one or more EMRs comprise the information; or
42(e) the information is self-reported by the subject.
It is unclear how these recited limitations relate to the prior cited method and provide further boundaries for the claimed limitations.
In addition to the above indefiniteness, the above phrase are indefinite because “the biological sample” and “the analytes quantified in (a)(ii) is from step (a) of claim 1 and claim 34 is further limiting step (b).
The above phrases are indefinite because it is unclear what is meant by “the likelihood that high” or “the information comprises a severity of the immune mediated inflammatory disease or a symptom thereof”. Both of these phrases are unclear and do not provide clear understanding for the claim limitations.
For the sake of compact prosecution, examiner will interpret the biological sample and analytes quantified in (a)(ii) to be further limiting to step (a) of claim 1 and will interpret the reference of any severity of immune-mediated inflammatory diseases or symptoms to be drawn to the other limitations.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefore, subject to the conditions and requirements of this title.
8. Claims 1-3, 8-9, 16-17, 20-22, 25-27, 29-30, 34-35, 42, 48-49, and 51 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception (i.e., a law of nature/ a natural phenomenon) without significantly more.
The claims recite a method of treating an immune mediated inflammatory disease in a subject, the method comprising:
(a) analyzing a biological sample obtained from a subject with an immune-mediated inflammatory disease, wherein the analyzing comprises:(i) obtaining or having obtained the biological sample from the subject; and (ii) quantifying or having quantified analytes in the biological sample, wherein the analytes comprise: (1) a level of a biologic drug, (2) a level of autoantibodies against the biologic drug, and (3) a level of albumin, wherein the subject has received a treatment for the immune-mediated inflammatory disease that comprises a current dose of the biologic drug administered to the subject at a current inter-dose interval;
(b) determining a likelihood of achieving a pre-specified threshold concentration of the biologic drug in the subject based, at least in part, on (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current dose of the biologic drug and the current inter-dose interval; and
(c) if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is above 50%, then:(1) administering the current dose of the biologic drug to the subject at the current inter-dose interval; or (2) administering a dose of the biologic drug that is (i) lower than the current dose to the subject at the current inter-dose interval, (ii) the same as the current dose to the subject at an inter-dose interval that is longer than the current inter-dose interval, or (iii) lower than the current dose to the subject at an inter-dose interval that is longer than the current inter-dose interval;
(d) if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is below 50%, then administering a dose of the biologic drug that is (i) higher than the current dose to the subject in the current inter-dose interval, (ii) the current dose at an inter-dose interval that is shorter than the current inter-dose interval, or (iii) higher than the current dose to the subject in the inter-dose interval that is shorter than the current inter-dose interval; or
(e) if the dose of the biologic drug in (d) is above a maximum dose and the inter-dose interval in (d) is less than or equal to a minimum inter-dose interval, then discontinuing the treatment comprising the biologic drug.
Claim 25 is further drawn to if the treatment comprising the biologic drug is discontinued in (e), then administering to the subject another biologic drug that differs from the biologic drug.
The claimed method has four possible outcomes: (1) identifying the patient as responsive to a biologic drug and administering the biologic drug at its current dose and inter-dose interval; (2) identifying the patient as responsive to a biologic drug and decreasing dose and/or increasing the inter-dose interval; (3) identifying the patient as not responsive to a biologic drug at current dose and inter-dose interval and increasing the dose or decreasing the inter-dose interval to achieve a response to the biologic drug; or (4) identifying the patient as non-responsive to a biologic drug after the dose is at its maximum dose level and minimum inter-dose interval and discontinuing treatment and further in claim 25 administering another biologic drug after discontinuation of treatment. Thus, the claims are directed to the judicial exception of naturally occurring serum analytes in a biological sample of a subject with an immune-mediated inflammatory disease and a correlation to the likelihood of response to a biologic agent at a specific dose and inter-dose interval.
In outcome (1), the claims recite continuing to administer the same biologic drug at the same dose and interval that the subject is already receiving. The claimed method simply observes the naturally occurring phenomenon/law of nature during a course of continued treatment. The judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature while continuing to administer the same biologic drug at the same dose and interval. For the reasons stated above, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to quantify or obtain data from quantified analytes in a biological sample that are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception.
In outcomes (2) and (3), the claims recite continuing to administer the same biologic drug at either the same dose, the same interval, a lower dose, a higher dose, a shorter interval, or a longer interval. The judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature while continuing administration with the same biologic drug. For the reasons stated above, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to quantify or obtain data from quantified analytes in a biological sample that are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception. The claimed changes in dose or frequency of administration after observing the naturally occurring phenomenon/law of nature do not amount to significantly more than the judicial exception because these types of dose/frequency changes are limitations that are well-understood, routine, conventional activity in the field of treating inflammatory diseases and do not amount to significantly more than the judicial exception (see MPEP 2106.05(d)).
In outcome (4), this judicial exception is not integrated into a practical application because the claims recite only the detection or observation of a naturally occurring phenomenon/law of nature, which is data gathering to observe the naturally occurring phenomenon/law of nature without applying the data to a practical application. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims recite use of routine laboratory procedures to detect and observe naturally occurring serum analytes in a biological sample. The steps of quantifying or having quantified analytes in the biological sample are considered known, routine steps and are typically taken by those in the field to perform testing of a sample and are not elements that are sufficient to amount to significantly more than the judicial exception. For example, Rosario et al. (US2019/0255172 A1, pub. 8/22/2019), Rutgeerts, et al. (Alimentary Pharm. And Thera., 2006, 23:451-463), Bar-Yoseph, et al. (Alimentary Pharm and Thera., 2017, 47:212-218), Lopez-Ibanez et al. (Gastroenterol. Hepatol., 2016, 39(4):265-272), Moots et al. (PLOS One, 2017, 12(4):e0175207), Mok et al. (Clin Rheumatol, 2013, 32:1429-1435), and Laine et al. (Biologics: Targets and Therapy, 2016, 10:67-73) all teach and demonstrate routine methods of quantifying analytes in a biological sample for analyzing the responsiveness of a subject to a biologic drug including drug concentration, drug autoantibodies, and albumin levels. Routine data gathering in order to observe a natural phenomenon/ natural principle does not add a meaningful limitation to the method as it would be routinely used by those of ordinary skill in the art in order to observe the natural phenomenon/ natural principle, and it fails to narrow the scope of the claims such that others are not foreclosed from using the law of nature/natural phenomenon. Methods of detecting natural phenomenon preempt all practical uses of it as others must use/detect the natural phenomenon to apply it to any other correlations, diagnosis, prognosis, therapeutic response, monitoring, etc.
Claim 25 also fails to add significantly more to the judicial exception. In outcome (4), this judicial exception is not integrated into a practical application because the step of “administering to the subject another biologic drug that differs from the biologic drug” in claim 25 are generic instructions to apply the judicial exception and does not amount to significantly more that the judicial exception. It is a limitation that is well-understood, routine, conventional activity in the field of treating immune mediated disorders and does not amount to significantly more than the judicial exception (see MPEP 2106.05(d)). Generic treatment steps are no more than appending conventional steps specified at a high level of generality, are a generic direction to “apply it,” and fail to supply inventive concept to the judicial exception. The step of “administering to the subject another biologic drug that differs from the biologic drug” in claim 25 does not apply or use the judicial exception to affect a particular treatment (see MPEP 2106.05(f)).
To obviate the rejection, there must be at least one additional element or physical step that applies, relies on, or uses the natural principle so that the claim amounts to significantly more than the judicial exception itself. The claimed method currently fails to provide a practical application of the judicial exception and fails to add any elements that amount to significantly more than the judicial exception.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
9. Claims 1-3, 16, 20-22, 26-27, 29-30, 34-35, 42, 48-49, and 51 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Rosario (US2019/0255172 A1, pub. 8/22/2019) as evidenced by Rosario, et al. (Aliment Pharmacol Ther, 2015, 42:188-202).
Rosario discloses a method for treating an immune mediated inflammatory disease in a subject (pg. 2 [0015]), the method comprising:
(a) analyzing a biological sample obtained from a subject with an immune-mediated inflammatory disease, wherein the analyzing comprises: (i) obtaining or having obtained the biological sample from the subject; and (ii) quantifying or having quantified analytes in the biological sample, wherein the analytes comprise: (1) a level of a biologic drug (pg. 7 [0053]), (2) a level of autoantibodies against the biologic drug (pg. 12 [0087]), and (3) a level of albumin (pg. 7 [0053]), wherein the subject has received a treatment for the immune-mediated inflammatory disease that comprises a current dose of the biologic drug administered to the subject at a current inter-dose interval (pg. 5 [0044]); (See also [0018], [0053] also claims 46, 53, and 55-56).
(b) determining a likelihood of achieving a pre-specified threshold concentration of the biologic drug in the subject based, at least in part, on (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current dose of the biologic drug and the current inter-dose interval (pg. 7 [0053]); and
(c) if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is above 50%, then:(1) administering the current dose of the biologic drug to the subject at the current inter-dose interval; (pg. 14 [0112]);
(d) if the likelihood of achieving the pre-specified threshold concentration of the biologic drug is below 50%, then administering a dose of the biologic drug that is (i) higher than the current dose to the subject in the current inter-dose interval (pg. 14 [0113]).
Regarding claims 2-3, Rosario discloses the method wherein the biologic drug is a monoclonal antibody. (pg. 2 [0017]).
Regarding claim 16, Rosario discloses the predetermined threshold concentration of the biologic drug comprise between 1 mg/L and 10 mg/L. (pg. 7 [0053] using µg per mL which is the same as mg/L, i.e. 1 µg/mL = 1 mg/L).
Regarding claims 20-22, Rosario discloses using the body weight of the subject and the albumin concentration to determine antibody clearance (pg.9 [0068]) and the combination of the clearance rate with the antibody concentration to determine whether the subject has poor prognostic factor of pharmacokinetic origin (PPFPK). (pg. 5 [0046]).
Regarding claims 26, 34-35, and 42, Rosario discloses determining the likelihood of achieving the pre-specified threshold concentration of the biologic drug comprises applying an algorithm to the analytes quantified in (a)(ii) where the biological sample is serum, and the weight of the subject. (See Rosario, pg. 5 [0046]). Rosario also discloses the method of treatment where the severity of the immune-mediated inflammatory disease comprises a disease remission, a disease recurrence, and a disease type. (See Rosario, pg. 2 [0015], [0017]).
Regarding claims 27 and 29-30, Rosario discloses wherein the determining the likelihood of achieving the pre-specified threshold concentration of the biologic drug comprises applying an algorithm, wherein the algorithm is a Naïve Bayes classifier algorithm and comprises a model compromising establishing a first set of parameter estimates from a reference population that has received the biologic drug for treatment of the immune-mediated inflammatory disease, deriving a second set of parameter estimates for the model based at least in part on the first set of parameter estimates, and inputting data comprising the analytes quantified in the biological sample obtained from the subject into the model and the current dose of the biologic drug and the current inter-dose interval and interrogating the model based on the data, wherein the subject is nota part of the reference population. (See Rosario, Example 2, which cites Rosario et al. (2015) for the source of the population pharmacokinetic model). Rosario et al. (2015) further discloses the data for the population pharmacokinetic model uses C-reactive protein, body weight, and body mass index. (See Rosario, et al. (2015) pg. 190 column 2 paragraph 2).
Regarding claims 48-49, Rosario discloses the method wherein the immune mediated disease is inflammatory bowel disease including ulcerative colitis and Crohn’s disease. (pg. 2 [0017]). Rosario also discloses using the method for the severity of the immune-mediated inflammatory disease of inflammatory bowel disease comprising a disease type- specifically ulcerative colitis and Crohn’s disease
Regarding claim 51, Rosario discloses the method wherein: (a) the subject has received the treatment comprising the current dose of the biologic drug administered to the subject at the current inter-dose interval for at least 14 contiguous weeks (pg. 8 [0062]); (b) the subject has received the treatment regimen comprising the current dose of the biologic drug administered to the subject at the current inter-dose interval at least once (pg. 5 [0045]); or (c) the biological sample is obtained in (a)(i) up to 20 days following a fast administration of the biologic drug at the current dose (pg. 8 [0060]).
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.
10. Claims 8-9, 17, and 25 are rejected under 35 U.S.C. 103 as being unpatentable over Rosario (US2019/0255172 A1, pub. 8/22/2019) as applied to claims 1-3, 16, 20-22, 26-27, 29-30, 34-35, 42, 48-49, and 51 above, and further in view of Rutgeerts, et al. (Alimentary Pharm. And Thera., 2006, 23:451-463) and Bar-Yoseph, et al. (Alimentary Pharm and Thera., 2017, 47:212-218).
The limitations of claims 1-3, 16, 20-22, 26-27, 29-30, 34-35, 42, 48-49, and 51 are disclosed by Rosario as discussed above.
Rosario did not disclose the method wherein the biologic drug is infliximab given at the dose of 3 to 15 mg/kg and the inter-dose interval of every 4 to 12 weeks and where the predetermined threshold concentration of infliximab is 5 mg/L to 10 mg/L and if treatment of the biologic is discontinued another biologic drug is administered.
Rutgeerts discloses a method of treating Crohn’s disease using infliximab at a dose of 5 mg/kg at weeks 2 and 6 during induction and then every 8 weeks during maintenance treatment. (See Rutgeerts, “Summary”). Rutgeerts also teaches that 30% of refractory Crohn’s disease patients have been resistant to infliximab therapy and suggests the identification of predictors for response to infliximab therapy is important to optimize the use of infliximab. (See Rutgeerts, pg. 454).
Rutgeerts does not disclose a predetermined threshold concentration of infliximab is 5 mg/kg to 10mg/kg and treatment of another biologic drug if treatment of infliximab is discontinued.
Bar-Yoseph discloses a study of predictive biomarkers- including serum drug concentration and anti-drug antibodies- for infliximab response. Infliximab responders were observed to have a drug concentration of 5.5-16.8 mg/L (reported in µg/mL which converts to the same number in mg/L) which was significantly higher than infliximab non-responders. (See Bar-Yoseph, pg. 214, 216 Tables 1 and 2).
Bar Yoseph also discloses that among 35 infliximab non-responders who discontinued treatment, 7 reported receiving treatment of another biologic 3 months post-infliximab failure and 6 reported responsiveness to another biologic agent at one-year post-infliximab failure. (See Bar-Yoseph, pg. 213 “Results”)
It would have been prima facie obvious to a person of ordinary skill in the art prior to the effective filing date to use the method of Rosario with the teachings of Rutgeerts and Bar-Yoseph to use infliximab with the method of predicting successful response to therapy as claimed in the present invention. It would have been obvious because all references are using monoclonal antibodies to treat Crohn’s disease, Rutgeerts discloses the treatment regimen used and suggests developing predictive biomarkers and Bar-Yoseph observed drug concentrations at the level of the pre-specified threshold concentration for infliximab. Therefore, it would have been obvious to a person of ordinary skill in the art to apply the method of Rosario with the teachings and suggestions of Rutgeerts and Bar-Yoseph with a reasonable expectation of success at developing a successful method for predicting infliximab response as claimed in the present claimed invention.
Double Patenting
11. 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.
12. Claims 1-3, 8-9, 16-17, 20-22, 25-27, 29-30, 34-35, 42, 48-49, and 51 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-4, 85, 423-424, 427, and 431-432 of copending Application No. 19122489 (hereinafter App. ‘489) in view of Bar-Yoseph, et al. (Alimentary Pharm and Thera., 2017, 47:212-218) and Rosario (US2019/0255172 A1, pub. 8/22/2019).
App. ‘489 claims a method for treating an immune mediated inflammatory disease in a subject, the method comprising:
(a) analyzing one or more biological samples obtained from a subject receiving a biologic drug for treatment of an immune-mediated inflammatory disease, wherein the analyzing comprises: (i) obtaining or having obtained the one or more biological samples from the subject prior to a third dose of the biologic drug in an induction phase of the treatment; and (ii) quantifying or having quantified analytes in the biological sample, wherein the analytes comprise: (1) a level of the biologic drug, (2) a level of autoantibodies against the biologic drug, and (3) a level of albumin, wherein the subject has received the treatment for the immune-mediated inflammatory disease that comprises a current dose of the biologic drug administered to or by the subject at a current inter-dose interval; and
(b) determining an estimated concentration time course curve of the biologic drug in the subject based, at least in part on, (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current dose of the biologic drug and the current inter-dose interval; and(c) if the estimated concentration of the biologic drug on the time course curve at one or more comparing time points is at or near, or above a pre-specified threshold concentration, then: (1) administering the current dose of the biologic drug to the subject at the current inter- dose interval; or (2) administering a dose of the biologic drug that is (i) lower than the current dose to the subject at the current inter-dose interval, (ii) the same as the current dose to the subject at an inter-dose interval that is longer than the current inter-dose interval, or (iii) lower than the current dose to the subject at an inter-dose interval that is longer than the current inter-dose interval; (d) if the estimated concentration of the biologic drug on the time course curve at the one or more comparing time points is below the pre-specified threshold concentration, then administering a dose of the biologic drug that is (i) higher than the current dose to the subject in the current inter-dose interval, (ii) the current dose at an inter-dose interval that is shorter than the current inter-dose interval, or (iii) higher than the current dose to the subject in the inter-dose interval that is shorter than the current inter-dose interval; or (e) if (i) the estimated concentration of the biologic drug on the time course curve at the one or more comparing time points is below the pre-specified threshold concentration, (ii) the dose of the biologic drug in (d) is above a maximum dose, and (iii) the inter-dose interval in (d) is less than or equal to a minimum inter-dose interval, then discontinuing the treatment comprising the biologic drug; wherein the one or more comparing time points is after the one or more biological samples is obtained from the subject; or
(b) determining an estimated dose and an estimated inter-dose interval of the biologic drug for the subject based, at least in part on, (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current dose of the biologic drug and the current inter-dose interval, wherein the estimated dose at the estimated inter-dose interval is predicted to result in a pre-specified threshold concentration of the biologic drug in the subject at one or more comparing time points; and (c) administering the biologic drug to the subject at the estimated dose and estimated inter- dose interval; in claims 1-2 which is directed to present claim 1.
App. ‘489 claims a method for identifying an optimal dose and inter-dose interval for treating an immune mediated inflammatory disease in a subject, the method comprising:
(a) analyzing one or more biological samples obtained from a subject receiving a biologic drug for treatment of an immune-mediated inflammatory disease, wherein the analyzing comprises:(i) obtaining or having obtained the one or more biological samples from the subject prior to a third dose of the biologic drug in an induction phase of the treatment; and (ii) quantifying or having quantified analytes in the biological sample, wherein the analytes comprise: (1) a level of the biologic drug, (2) a level of autoantibodies against the biologic drug, and (3) a level of albumin, wherein the subject has received the treatment for the immune-mediated inflammatory disease that comprises a current dose of the biologic drug administered to or by the subject at a current inter-dose interval; and
(b) determining an estimated concentration time course curve of the biologic drug in the subject based, at least in part on, (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current weight-based dose of the biologic drug and the current inter-dose interval, wherein the optimal dose and inter-dose interval is identified such that the estimated concentration of the biologic drug on the time course curve at one or more comparing time points is above a pre-specified threshold concentration; or
(b) determining an estimated dose and an estimated inter-dose interval of the biologic drug for the subject based, at least in part on, (1) the level of the biologic drug, the level of the autoantibodies, and the level of albumin quantified in (a)(ii), and (2) the current dose of the biologic drug and the current inter-dose interval, wherein the estimated dose at the estimated inter-dose interval is predicted to result in a pre-specified threshold concentration of the biologic drug in the subject at one or more comparing time points; in claims 3-4 which is directed to present claim 1.
While App. ‘489 claims 1-4 do not recite “determining a likelihood of achieving a pre-specified threshold concentration” claims 1 and 3 recite “determining an estimated concentration time course curve” which is a method of determining a likelihood of achieving a pre-specified threshold concentration and claims 2 and 4 recite “determining an estimated dose and an estimated inter-dose interval of the subject” using the same analytes recited in step (a)(ii) which in present claim 1 the pre-specified threshold concentration is used to determine an estimated dose and an estimated inter-dose interval of the biologic drug. Claims 1-4 also use the pre-specified concentration threshold to determine dose and inter-dose interval to the biologic drug which is an obvious version of the present claim 1’s steps (c), (d), and (e). Thus, claims 1-4 of App. ‘489 are obvious versions of the present claim 1.
App. ‘489 claims the biologic drug is a monoclonal antibody or antigen-binding fragment in claim 423 which is directed to present claims 2-3.
App. ‘489 claims the method of determining the estimated concentration time course curve of the biologic drug is based on the weight of the subject, clearance rate of the biologic drug in the subject estimated based, at least in part, on the weight of the subject and the level of albumin quantified in (a)(ii); or (c) whether the subject has a poor prognostic factor of pharmacokinetic origin (PPFPK), wherein the PPFPK is determined based, at least in part, on the level of the biologic drug quantified in (a)(ii) and the clearance rate in claim 424 which is directed to present claims 20-22, 30, and 34.
App. ‘489 claims the biologic drug is infliximab at a current dose of 3 to 15 mg/kg and the current inter-dose interval is every four to twelve weeks and where the pre-determined threshold concentration is about 5mg/L to about 10 mg/L in claim 427 which is directed to present claims 8-9 and 16-17.
App. ‘489 claims a method for identifying a dose and an inter-dose interval for achieving a biologic drug concentration value in a subject comprising (a) initializing a model of a biologic drug concentration profile for a biologic drug, wherein the model comprises data received from a reference population that were or currently are being treated with the biologic drug for treatment of an immune-mediated inflammatory disease;(b) generating subject specific parameters relating to pharmacokinetic performance of the biologic drug in the subject, wherein generating the subject specific parameters is performed using one or more biological samples obtained from the subject prior to a third dose of the biologic drug in an induction phase of the treatment of the immune-mediated inflammatory disease;(c) simulating the biologic drug concentration profile for the subject based on the subject specific parameters and the data from the reference population; and(d) estimating a dose of the biologic drug at an inter-dose interval to achieve the threshold biologic drug concentration value in the subject at one or more comparing time points with the model, wherein the threshold biologic drug concentration is sufficient to treat the immune-mediated inflammatory disease in the subject in claim 85 which is directed to claims 26 and 29.
App. ‘489 claims a method for determining the estimated concentration time course curve of the biologic drug in the subject utilizing a model comprising: (i) establishing a first set of parameter estimates from a reference population, wherein the reference population has received the biologic drug for treatment of the immune-mediated inflammatory disease;(ii) deriving a second set of parameter estimates for the model based at least in part on the first set of parameter estimates established in (i);(iii) inputting data comprising the analytes quantified in the one or more biological samples obtained from the subject into the model, the current dose of the biologic drug and the current inter-dose interval, a level of C-Reactive Protein (CRP), a level of interleukin 6 (IL-6),weight or BMI of the subject, or a combination thereof; and(iv) interrogating the model based at least in part on the data, wherein the subject is not a part of the reference population in claim 431 which is directed to present claims 26 and 29.
App. ‘489 claims where the immune-mediated inflammatory disease comprises an inflammatory bowel disease (IBD), comprising Crohn's disease (CD) or ulcerative colitis (UC), rheumatoid arthritis (RA), cytokine release syndrome, multiple sclerosis (MS), ankylosing spondylitis (AS), lupus, plaque psoriasis, atopic dermatitis, gout, migraine, cancer, or a neoplasm in claim 432 which is directed to present claims 48-49.
App. ‘489 does not claim a method where the algorithm is a naïve Bayes classifier algorithm or a Metropolis Hastings algorithm, wherein:(a) the biological sample comprises a serum sample;(b) the likelihood that high is equal to or about 90%;(c) the analytes quantified in (a)(ii) further comprise a level of C-Reactive Protein (CRP);(d) the analytes quantified in (a)(ii) further comprise interleukin 6 (IL-6);(e) the analytes quantified in (a)(ii) are quantified with an assay comprising a mobility shift assay or a solid-phase immunoassay; or (f) further comprising receiving information about the subject, wherein the information comprises a severity of the immune-mediated inflammatory disease or a symptom thereof; or wherein: (a) the severity of the immune-mediated inflammatory disease comprises a disease remission, a disease recurrence, a disease type, or any combination thereof; (b) the severity of the symptom of the immune-mediated inflammatory disease comprises a frequency of the symptom, a type of the symptom, or a combination thereof; (c) the severity of the immune-mediated inflammatory disease or symptom thereof is based on a clinical disease activity index (CDAI) score; (d) the receiving the information about the subject comprises receiving one or more electronic medical records (EMRs), wherein the one or more EMRs comprise the information; or (e) the information is self-reported by the subject.
App. ‘489 does not claim the method wherein if treatment is determined to be discontinued then administration to the subject of another biologic drug or wherein the subject has received the treatment comprising the current dose of the biologic drug administered to the subject at the current inter-dose interval for at least 14 contiguous weeks; the subject has received the treatment regimen comprising the current dose of the biologic drug administered to the subject at the current inter-dose interval at least once; or the biological sample is obtained in (a)(i) up to 20 days following a last administration of the biologic drug at the current dose.
Rosario discloses determining the likelihood of achieving the pre-specified threshold concentration of the biologic drug comprises applying an algorithm, wherein the algorithm is a Naïve Bayes classifier algorithm (See Rosario, Example 2) to the analytes quantified in (a)(ii) where the biological sample is serum. (See Rosario, pg. 5 [0046]). Rosario also discloses the method of treatment where the severity of the immune-mediated inflammatory disease comprises a disease remission, a disease recurrence, and a disease type. (See Rosario, pg. 2 [0015], [0017]).
Bar-Yoseph discloses a study where infliximab responders were compared to infliximab non-responders to determine predictors of successful responsive therapy. Both populations received induction treatment regimen of a dose at 0, 2, and 6 weeks and then had samples drawn and tested at 2 and 6 weeks, following at least one dose at current dose and current inter-dose intervals and the biological samples obtained at two weeks were within 20 days of the last administration of the biologic drug at current dose. (See Bar-Yoseph, pg. 213 “Methods”). Bar Yoseph also discloses that among 35 infliximab non-responders who discontinued treatment, 7 reported receiving treatment of another biologic 3 months post-infliximab failure and 6 reported responsiveness to another biologic agent at one-year post-infliximab failure. (See Bar-Yoseph, pg. 213 “Results”).
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the method disclosed in App. ‘489 with the method disclosed in Rosario for the present claimed method. It would have been obvious because both App. ‘489 and Rosario are disclosing methods of treatment for inflammatory bowel disease, the Naives Bayer algorithm is well known and simple to apply, testing serum for the specified tests is well known and routine within IBD treatment and prognosis, and IBD is known to be a complex severe disease with recurrence and remission periods and different disease types. Therefore, it would have been obvious to a person of ordinary skill in the art prior to the effective filing date to combine the methods of App. ‘489 with the methods of Rosario to develop the present claimed method with a reasonable expectation of success.
It would have been prima facie obvious for a person of ordinary skill in the art prior to the effective filing date to use the method of App. ‘489 with the disclosure of Bar-Yoseph for the method of the instant claimed invention. It would have been obvious because the induction dose and dose interval used in Bar-Yoseph is standard induction treatment for infliximab and treatment with another biologic agent after discontinuation of treatment is standard and Bar-Yoseph provides evidence it is successful treatment option. Therefore, it would have been obvious for a person of ordinary skill in the art prior to the effective filing date to apply the disclosed methods of Bar-Yoseph to the method of App. ‘489 with a reasonable expectation of success at developing the method of the present claimed invention.
This is a provisional nonstatutory double patenting rejection.
Conclusion
13. Claims 1-3, 8-9, 16-17, 20-22, 25-27, 29-30, 34-35, 42, 48-49, and 51 are rejected.
14. Any inquiry concerning this communication or earlier communications from the examiner should be directed to LINDSAY DUNN whose telephone number is (571)272-5825. The examiner can normally be reached Monday-Friday 8-4:30.
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/LINDSAY DUNN/ Examiner, Art Unit 1642
/Laura B Goddard/ Primary Examiner, Art Unit 1642
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