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 .
Applicants filed response on 7/21/2025 has been received.
Applicant’s election without traverse of Group I with species anti-IA2 IgG, and anti-beta2glycoprotein IgG in the reply filed on 12/11/2024 is acknowledged.
Claims 2-7, 10-25, 27-28, 30-39, 41-44, 46-52, 54-60, 62-68, 70-72, 74-75, 77, 79, 81, 83-93, 95, 97, 99-101, 103-107 and 109-115 have been cancelled.
Claims 1, 8-9, 26, 29, 40, 45, 53, 61, 69, 73, 76, 78, 80, 82, 94, 96, 98, 102 and 108 are pending.
Claims 45, 53, 61, 76, 78, 80, 98 and 102 are withdrawn from further consideration. Note, due to the election of species anti-IA2 IgG, and anti-beta2glycoprotein IgG, and with type 1 diabetes, claim 102 is withdrawn. Moreover, kit claim 82 is added according to the agents used for detection of anti-IA2 IgG, and anti-beta2glycoprotein IgG.
Currently, claims 1, 8-9, 26, 29, 40, 69, 73, 82, 94, 96 and 108 are under examination.
The rejection on claim 69 and 73 under 35 USC 101, judicial exception remains (See below).
Claim Rejections - 35 USC § 101
“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 therefor, subject to the conditions and requirements of this title.”
The claimed invention is not directed to patent eligible subject matter. Based upon an analysis with respect to the claim as a whole, claim(s) 69 and 73 do not recite something significantly different than a judicial exception. The rationale for this determination is explained below:
The first step requires that the claimed invention ‘‘must be directed to one of the four statutory categories’’, namely process, machine, manufacture or composition, and the second step requires that the invention ‘‘must not be wholly directed to subject matter encompassing a judicially recognized exception’’, namely a law of nature, a natural phenomenon or an abstract idea (emphasis added).
Independent claim is directing to a method of measuring the levels of one or more ; comparing the results to the levels of the same biomarker(s) from control subjects, and correlating the results to
With regard to Eligibility step 1 – Yes, the claimed invention is a process (method) which is one of the four statutory categories of invention.
With regard to Eligibility Step 2A prong 1: Is the claim directed to a law of nature, a natural phenomenon (product of nature) or an abstract idea? Yes, the claims recite an abstract idea, law of nature or natural phenomenon.
Here the law of nature refers to the (1) measuring natural molecules from a subject, i.e. anti-IA2 IgG and anti-beta2glycoprotein IgG in samples, and (2) correlating higher levels of anti-IA2 IgG and anti-beta2glycoprotein IgG for effective treatment by alefacept. Therefore, the natural relationship is the biomarker(s) correlating with a “condition” under judicial exception. (See Mayo Collaborative Servs. v. Prometheus Laboratories, Inc., 132 S.Ct. 1289 (2012) ,similarly to the Prometheus case wherein the level of 6–thioguanine less than about 230 pmol per 8x108 red blood cells indicates a need to increase the amount of said drug subsequently administered to said subject and wherein the level of 6–thioguanine greater than about 400 pmol per 8x108 red blood cells indicates a need to decrease the amount of said drug subsequently administered to said subject.)
Under Step 2A prong 2, whether the claims recite additional elements that integrate the judicial exception into a practical application. The answer is No because no additional step or feature is recited in the claims. Note, the “reporting that the treatment with alefacept is effective”. This step is not one that applies, relies on, or uses the judicial exception (See Mayo Collaborative Servs. v. Prometheus Laboratories, Inc., 132 S.Ct. 1289 (2012)). Moreover the treatment of alefacept, i.e. prior and post of treatment resembling to the Prometheus scenario (Mayo Collaborative Servs. v. Prometheus Labs., Inc., 566 U.S. 66, 71, 101 USPQ2d 1961, 1965 (2012) where a treatment was administered to the patient followed by measuring related drug-metabolite. This administering step does not provide a significant weight to the claim amounting more than law of nature. It is because this step is not one that applies, relies on, or uses the judicial exception, i.e. “reporting that the treatment with alefacept is effective). (Vanda Pharmaceuticals Inc. v. West-Ward Pharmaceuticals (2018)). The step of treating the subject is merely part of data-gathering process. One clinician cannot determine how a treatment works unless administering the treatment to the subjects followed by measuring the biomarkers (MPEP 2106.05(a)). In another word, the initial treatment testing here is not the step one clinician does in response to the law of nature, i.e. identified autoantibodies of IA2 and beta2-glycoprotein in patient and treating the identified patient accordingly (See above Vanda Pharmaceuticals case holding). No additional element adds to the claim amounting significantly more than mere judicial exception.
Under Step 2B, whether a claim amounts to significantly more. The answer is No. The instant steps, such as obtaining samples, measuring biomarkers, comparing and administering are well-understood, routine, conventional activity in the field and add insignificant extra-solution activity to the judicial exception. For instance, the specification illustrates using conventional immunoassay (see background and section 0089). These steps are recited at a high level of generality, and are necessary data gathering steps that feed into the determining step. One cannot do the determining step without getting the data. This weighs against it being significantly more.
Applicants’ Remarks are summarized below:
“While Applicant does not agree with the Office's analysis under Step 1 and Step 2A as set forth on page 3 of the NFOA, in the interest of compact prosecution, Applicant focuses on Step 2B, which alone is enough to render the rejected claims patent eligible. Under Step 2B, the claimed methods amount to significantly more than the judicial exception alleged by the Office.
It was the current Inventors that determined the specific biomarkers predictive of the effectiveness or responsiveness to alefacept treatment in patients with Type 1 diabetes. Detection of one or more of the specific biomarkers herein "allows for an earlier determination of the effectiveness of alefacept treatment than traditional clinical indicators." Specification, [0138]. It is important to be able to accurately determine whether a subject is a candidate for treatment with an immunosuppressive drug like alefacept, and to detect early in treatment if the drug is effective. This determination allows the prescribing physician to avoid excessive or unnecessary immunosuppression, which can lead to unwanted side effects in the subject. The ability to predict the effectiveness of treatment, and thus determine if a subject with Type 1 diabetes is a candidate for treatment, also reduces excess immunosuppression. The specific method and combination of biomarkers described herein together thus amount to significantly more than the judicial exception”.
Applicant’s arguments have been considered but are not persuasive.
Applicants focus on Step 2B for analysis of judicial exception under 35 USC 101. However applicants merely brought out the “novelty” of using the recited biomarker autoantibodies, i.e. anti-IA2 and anti-beta2-glycoprotein, in early determination of the effectiveness of alefacept treatment. Examiner disagrees.
The “novelty” test, in general, refers to the improvements to the functioning of a computer for the assay of the biomarkers, or a particular novel machine for the assay, or performing the assay in a particular environment or different state or adding a specific limitation other than what is well-understood, routine, or conventional activity in the field (see 2019 Revised Guidance for Determining Subject Matter Eligibility, page 20/29; See https://www.uspto.gov/sites/default/files/documents/20190207_PPAC_Revised_Guidance_for_Determining_Subject_Matter_Eligibility.pdf). In another word, the assays (e.g. immunoassays) for measuring the autoantibody biomarkers are well understood and conventional to one ordinary skilled person in the art. Therefore the steps in claims are insignificant extra solution activity, and would not mount significantly more than law of nature.
The rejections on claims 1, 8-9, 26, 29, 40, 82, 94, 96 and 108 are rejected under 35 U.S.C. 103 as being unpatentable over Thoreau (Acta Derm Venereol. 2017 97:408-409; IDS reference) in view of Kiss (Clin. Exp. Immunol. 1999 117:574-579) and Trebissou (J Cell Immunol 2019 1:12-15; publication September 19 2019) are maintained.
The current invention directs to a multiplexed assay, panel or kit for measuring two analyte from a biological sample. The two target molecule (elected species for prosecution thus far) are anti-IA2 IgG and anti-beta2-glycoprotein IgG.
Thoreau teaches measuring anti-IA2 IgG and anti-beta2-glycoprotein IgG from a diabetic patient’s blood sample (see Case report). However Thoreau does not explicitly reveal using binding reagents for determining the two analytes in the sample. Note, Thoreau states “laboratory tests” for determining the above two target molecules. Nevertheless such measurements are known and commonly practiced in the field.
For instance, Kiss teaches measuring anti-beta2glycoprotein IgG by immunological binding assay (See Abstract; Method).
Furthermore, Trebissou also teaches using immunological binding assay (commercial kit Euroimmun® , Germany) for determining anti-IA2 IgG in a biological sample from type I diabetic patient (see Methods). Taken together the above well-known immunological assay methods would have applied conventional immunological binding principle, i.e. binding domain of analyte with binding reagent followed by binding labeled reagent for detection (read on claims 8-9, 26, 29).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use the methods taught by Kiss and Trebissou to determine anti-IA2 IgG and anti-beta2-glycoprotein IgG with reasonable expectation of success because the well-known and commonly measured in the field and would have reasonable expectation of success (read on claims 1(A), 8-9, 40, 82(A), 94(L) and 108(A)).
Applicants’ Remarks are summarized below.
“However, Thoreau and Trebissou teach away from one another. Thoreau measures anti-IA2 IgG and anti-beta2-glycoprotein IgG in a Type 1 diabetic patient and finds that the patient was negative for both of these antibodies. (See Thoreau, Case Report).
Conversely, anti-IA2 IgG is measured as a marker of Type 1 diabetes in Trebissou, and it is shown that anti-IA2 IgG is present from 1 year to at least 9 years after diagnosis (See Introduction, Results (second paragraph), and Discussion). Thus, a person of ordinary skill in the art (POSA) would not look to Trebissou to modify the method of Thoreau for measuring anti- IA2 IgG and anti-beta2-glycoprotein IgG in a diabetic patient. Further, Kiss measures anti-beta2- glycoprotein antibodies with an immunological assay in patients with anti-phospholipid syndrome (APS) and does not refer to anti-beta2-glycoprotein antibodies in Type 1 diabetes patients. A POSA would thus not look to Kiss to modify the method of Thoreau and, in addition, Kiss does not overcome the deficiencies of the combination of Thoreau and Trebissou”.
Applicant’s arguments have been considered but are not persuasive.
Examiner would like to stress that the combination of Kiss and Trebissou additional references is NOT motivated and/or suggested for the purpose of diagnosis of type 1 diabetes. The main reference of Thoreau discloses detection on autoantibodies IgG against IA2 and beta2-glycoprotein, regardless whether any correlation, higher or lower changes between the two target molecules and type 1 diabetes. Basically Thoreau’s laboratory merely launched measuring for the two target molecules, albeit no explicit steps or assays were stated. Nevertheless Thoreau did not explicitly disclose steps and ingredient used for the performing the assay. This is the incentive that one ordinary skilled person would have been motivated to adapt or apply the well-known immunoassay, such as taught by Kiss and Trebisou, to determine the levels of the two target molecules from the patient in Thoreau. The issue is on what one ordinary skilled person without specific instruction or guidance from Thoreau would do “at the time of determining the autoantibodies from a patient’s blood sample”, not afterwards screening the results and deciding which biomarkers are useful for diagnosis. More important, the main claim 1 (multiplexed assay), claim 82 (kit), claim 94 (system) and claim 108 (assay method) do not direct to diagnosis (emphasis added). Under broadest reasonable interpretation, the components and key features in aforementioned claims are merely determining the two target molecules from a sample which have been shown obvious in the three references.
The rejection on claims 69 and 73 under 35 USC 112, first paragraph is withdrawn because of support from experimental data.
Claims 69 and 73 are free of prior art (but subject to judicial exception rejection). It is noted that biomarkers of diagnosing type 1 diabetes have been identified in the last few decades. However not every biomarker is suitable for monitoring efficacy of type 1 diabetes treatment. In the article “What are biomarkers” (Curr Opin HIV AIDS 2010 5: 463-466), Strimbu stated that “[m]ore recently, a large and well-publicized trial of the combination of two cholesterol-lowering drugs, ezetimibe and simvastatin, highlighted the risk of relying too much on biomarkers: although the combination treatment lowered subjects' cholesterol levels more than simvastatin alone, it did not lead to any improvement in atherosclerosis or overall mortality, calling into question a great deal previous research that depended on the assumption that lowering cholesterol necessarily lowered morbidity and mortality. In both these cases, as in many others, despite the best biological and statistical evidence, biomarkers that were “validated” even in a series of previous trials were found poor predictors of clinical outcomes.” (See page 4, middle portion)(emphasis added). Cholesterol is a well-known biomarker for cardiovascular disease. Targeting this molecule for treating cardiovascular disease has generated many studies in the field. However, the anticipation is not always as expected. In another word, not every “biomarker” (in diagnosis) is suitable for use as a tool in evaluating treatment. For instance, Feldman (US 20160025744) teaches measuring anti-IA2-IgG autoantibody for diagnosis of diabetes (section 0038, 0088; claims 1-10) and Kalousova (Prague Medical Report 2004 105:21-28) observed an elevation of anti-beta2-glycoprotein in type 1 diabetes patients (see Abstract). However the current application discovers that an elevated of anti-IA2 and anti-beta2-glycoprotein antibodies is associated with the positive response to the treatment of therapeutic drug alefacept. This shows that an actual clinical study needs to be employed to identify suitable biomarker(s) for monitoring therapeutic treatment.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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CHANGHWA J. CHEU
Primary Examiner
Art Unit 1678
/CHANGHWA J CHEU/Primary Examiner, Art Unit 1678