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
Applicant’s election without traverse of the invention of Group I, claims 1-2, 6, 10, 24, 26, 29, 171-173, 175, 178-179, and 183, and the species “GFAP and CDCP1” for the genus “set of biomarkers” in the reply filed on 05/07/2026 is acknowledged.
Claim Status
The amendment of 05/07/2026 has been entered. Claims 1-2, 6, 10, 24, 26, 29, 32, 34-35, 58-59, 171-173, 175, 178-179, and 183 are pending in this US patent application. Claims 32, 34-35, and 58-59 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, and claims 2, 6, and 10 are withdrawn from further consideration as being drawn to nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/07/2026.
Claims 1, 24, 26, 29, 171-173, 175, 178-179, and 183 are currently under examination and were examined on their merits.
Information Disclosure Statement
The information disclosure statement filed in this application on 05/07/2026 has been received and considered.
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 therefor, subject to the conditions and requirements of this title.
Claims 1, 24, 26, 29, 171-173, 175, 178-179, and 183 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a judicial exception without significantly more.
The statutory categories of invention under 35 U.S.C. 101 are processes, machines, manufactures, and compositions of matter. However, certain members of these categories constitute judicial exceptions, i.e., the courts have determined that these entities are not patentable subject matter. These judicial exceptions include abstract ideas, laws of nature, and natural phenomena. The Office released guidance on January 7, 2019 for the examination of claims reciting natural products under 35 U.S.C. 101 in light of the recent Supreme Court decisions in Association for Molecular Pathology v. Myriad Genetics, Inc. (569 U.S. ___, 133 S. Ct. 2107, 2116, 106 USPQ2d 1972 (2013)) and Mayo Collaborative Services v. Prometheus Laboratories (566 U.S. ___, 132 S. Ct. 1289, 101 USPQ2d 1961 (2012)). This guidance indicates that claims must pass an eligibility test to avoid rejection under 35 U.S.C. 101. Under this test, the product must (a) not be directed to a judicial exception or must (b) contain additional elements that amount to significantly more than the judicial exception itself.
‘Directed to a judicial exception’ analysis:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
Markedly different characteristics can be expressed as the product’s structure, function, and/or other properties. Non-limiting examples of characteristics that can determine the presence of a marked difference include biological or pharmacological functions or activities; chemical and physical properties; phenotype, including functional and structural characteristics; and structure and form, whether chemical, genetic, or physical.
Instant claim 1 recites a method comprising, in its full scope in light of Applicant’s elected species, a method of generating a prediction of multiple sclerosis disease progression by applying a predictive model to the expression levels of GFAP and CDCP1. The application of the predictive model represents an abstract idea, and the relationship between GFAP and CDCP1 expression levels and MS disease progression is a natural phenomenon, both of which are judicial exceptions. As such, claim 1 recites a judicial exception.
Claims 24, 26, 29, and 171-173 depend from claim 1 and limit claim 1 by reciting limitations of the predictive model, i.e., the abstract idea. As such, claims 24, 26, 29, and 171-173 also recite judicial exceptions.
Claims 175 and 178-179 depend from claim 1 and limit the step of obtaining the dataset, i.e., the extra-solution activity required to obtain the data used in the judicial exception. As such, claims 175 and 178-179 recite judicial exceptions.
Claim 183 depends from claim 1 and recites a step of selecting a therapy based on the prediction of claim 1, i.e., claim 183 recites an additional abstract idea (a step of making a decision), which is a judicial exception.
Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
The instant claims do not recite additional elements that integrate the judicial exceptions into practical applications because the instant claims do not recite any elements other than judicial exceptions and insignificant extra-solution activity (conventional steps of measuring biomarkers recited at high levels of generality that are required to provide the data used in the abstract ideas/natural correlations of the instant claims).
‘Significantly more’ analysis:
The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the claims do not recite any elements other than judicial exceptions and insignificant extra-solution activity that is well-understood, routine, and conventional (see prior art discussion below under Claim Rejections – 35 USC 103).
Therefore, claims 1, 24, 26, 29, 171-173, 175, 178-179, and 183 are directed to subject matter that is not patent-eligible and are rejected under 35 U.S.C. 101.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 24, 26, and 29 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The factors to be considered in determining whether a disclosure meets the enablement requirements of 35 U.S.C. 112, first paragraph, have been described in In re Wands, 858 F.2d 731, 8 USPQ2d 1400 (Fed. Cir., 1988). The court in Wands states, “Enablement is not precluded by the necessity for some experimentation, such as routine screening. However, experimentation needed to practice the invention must not be undue experimentation. The key word is ‘undue’, not ‘experimentation’” (Wands, 8 USPQ2sd 1404). Clearly, enablement of a claimed invention cannot be predicated on the basis of quantity of experimentation required to make or use the invention. “Whether undue experimentation is needed is not a single, simple factual determination, but rather is a conclusion reached by weighing many factual considerations” (Wands, 8 USPQ2d 1404). Among these factors are: (1) the nature of the invention; (2) the breadth of the claims; (3) the state of the prior art; (4) the predictability or unpredictability of the art; (5) the relative skill of those in the art; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
While all of these factors are considered, a sufficient amount for a prima facie case is discussed below.
(1) The nature of the invention and (2) the breadth of the claims:
Claim 1 is drawn to a method involving generating a prediction of multiple sclerosis disease progression by applying a predictive model to the expression levels of the plurality of biomarkers. Claim 24 depends from claim 1 and states that the prediction of multiple sclerosis disease progression is one of five particular measures. Thus, the claims taken together with the specification imply that claim 24 recites a method involving generating a brain parenchymal fraction value, an EDSS score, a PDDS score, a PROMIS score, or an MSRS-R score by applying a predictive model to the expression levels of a plurality of biomarkers.
(3) The state of the prior art and (4) the predictability or unpredictability of the art:
The brain parenchymal fraction value, EDSS score, PDDS score, PROMIS score, and MSRS-R score recited in claim 24 are specific measures of particular clinical characteristics of MS patients. See, for example, Huang et al. discussed below under Claim Rejections – 35 USC 103, which describes the EDSS as a measurement of patient disability as determined by a qualified neurologist. None of the scores recited in claim 24 (and its dependent claims 26 and 29, which recite particular characteristics of the scores) involve the measurement of the recited protein biomarkers in patient samples as recited in claim 1.
As such, the state of the prior art at the time of Applicant’s invention as demonstrated by Huang indicates that the prediction of multiple sclerosis disease progression by generating a brain parenchymal fraction value, an EDSS score, a PDDS score, a PROMIS score, or an MSRS-R score by applying a predictive model to the expression levels of a plurality of biomarkers was highly unpredictable.
(5) The relative skill of those in the art:
The relative skill of those in the art is high.
(6) The amount of direction or guidance presented and (7) the presence or absence of working examples:
Applicant provides no direction, guidance, or working examples on generating a brain parenchymal fraction value, an EDSS score, a PDDS score, a PROMIS score, or an MSRS-R score by applying a predictive model to the expression levels of a plurality of biomarkers.
(8) The quantity of experimentation necessary:
Considering the state of the art as discussed by Huang, the high unpredictability, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to generate a brain parenchymal fraction value, an EDSS score, a PDDS score, a PROMIS score, or an MSRS-R score by applying a predictive model to the expression levels of a plurality of biomarkers.
Therefore, claims 24, 26, and 29 are rejected under 35 U.S.C. 112(a) as failing to satisfy the enablement requirement.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 175, and 183 are rejected under 35 U.S.C. 103 as being unpatentable over US patent application publication 2019/0265254 filed by Bielekova et al., published 08/29/2019, in view of Enyindah-Asonye et al., Proc. Nat’l. Acad. Sci. USA 114(33): E6912-E6921 (2017).
Bielekova teaches a method of determining whether patient has MS or other types of inflammatory neurological diseases and/or whether an MS patient has progressive MS or RRMS by measuring and detecting an increase or decrease in one or more biomarkers capable of distinguishing patients with MS from patients with other neurological diseases and/or patients with progressive MS (PPMS or SPMS) from patients with RRMS (see entire document, including abstract, paragraph 0143, and paragraph 0308; cf. claim 1). The MS profile from the sample can be then compared using differential protein expression mapping, whereby relative expression levels of proteins at specific molecular weights are compared by a variety of statistical techniques and bioinformatic software systems; the expression of one or more controls is evaluated, such as a housekeeping protein. In this context "consist of" indicates that only the expression of the stated molecules is evaluated; the expression of additional molecules is not evaluated (paragraphs 0089 and 0275; cf. claim 1 [“…obtaining or having obtained a dataset comprising expression levels of a plurality of biomarkers”]). The measured biomarkers may include GFAP (page 27, Table 4; paragraph 0330; cf. claim 1 [“…wherein biomarker 1 is GFAP”]). Predictions for new observations are based on a majority vote of the total number of trees (for classification). Taking this “average" of the constructed trees can reduce the variance from single trees to improve the classification performance. Random Forests were used to build two classifiers: differentiating MS from non-MS (HD, OIND, NIND) and differentiating progressive MS (PPMS, SPMS) from RRMS) (paragraph 0319; cf. claim 1 [“…generating a prediction of multiple sclerosis disease progression by applying a predictive model to the expression levels of the plurality of biomarkers”]). The methods involve detecting biomarkers in a sample obtained from the subject, as well as administering appropriate therapy to the subject based on the detected biomarkers (paragraphs 0009 and 0109; cf. claims 175 and 183).
However, Bielekova does not teach the measurement of CDCP1 as one of the biomarkers in the method for evaluating whether a patient has MS or a particular type of MS.
Enyindah-Asonye teaches that CD318, also known as CDCP1, is a potential target for the diagnosis of MS (see entire document, including abstract and page E6913, left column, paragraph 1; cf. claim 1 [“…wherein biomarker 2 is CDCP1”]).
While Bielekova does not teach the measurement of CDCP1 as one of the biomarkers in the method for evaluating whether a patient has MS or a particular type of MS, it would have been obvious to one of ordinary skill in the art to include the measurement of CDCP1 in Bielekova’s diagnostic method of measuring biomarkers of MS because Enyindah-Asonye teaches that CDCP1 is a potential biomarker for the diagnosis of MS. One of ordinary skill in the art would have a reasonable expectation that measuring the levels of CDCP1, as taught by Enyindah-Asonye, in the patient samples of Bielekova would successfully result in obtaining information about the patient’s MS status.
Therefore, claims 1, 175, and 183 are rendered obvious by Bielekova in view of Enyindah-Asonye and are rejected under 35 U.S.C. 103.
Claims 1, 171-173, 175, 178-179, and 183 are rejected under 35 U.S.C. 103 as being unpatentable over US patent application publication 2019/0265254 filed by Bielekova et al., published 08/29/2019, in view of Enyindah-Asonye et al., Proc. Nat’l. Acad. Sci. USA 114(33): E6912-E6921 (2017), and Huang et al., Proc. Nat’l. Acad. Sci. USA 117(23): 12952-12960 (2020; published 09 June 2020).
As discussed above, claims 1, 175, and 183 are rendered obvious by Bielekova in view of Enyindah-Asonye. However, these references do not teach the inclusion of age and/or sex or an EDSS score in the evaluation of the patients (claims 171-173), nor do they teach that the biomarker levels were measured using a proximity extension assay (claims 178-179).
Huang teaches the investigation of protein biomarkers in samples from patients with multiple sclerosis, in addition to healthy controls and patients with other neurological diseases (see entire document, including page 12952, abstract). The levels of proteins in the samples were determined using a proximity extension assay, which is a high-throughput multiplex proteomic immunoassay (page 12953, left column, paragraph 3; page 12959, left column, paragraph 3; cf. claims 178-179). Protein associations to multiple sclerosis and disease-related characteristics, including an EDSS score, were analyzed using a multivariable linear regression model, adjusting for sex and age at sampling (page 12959, left column, paragraph 2, and right column, paragraph 1; cf. claims 171-173).
While Bielekova and Enyindah-Asonye do not teach the inclusion of age, sex, and/or disease duration or an EDSS score in the evaluation of the patients or the measurement of biomarker levels in patient samples using a proximity extension assay in the method of diagnosing MS based on biomarker levels rendered obvious by their teachings, it would have been obvious to one of ordinary skill in the art to do so because Huang teaches that these determinations of clinical characteristics and measuring biomarker levels with a proximity extension assay are useful in determining the relevance of protein levels in patient samples to the patient’s MS status. One of ordinary skill in the art would have a reasonable expectation that including the clinical characteristics and proximity extension assay of Huang in the method rendered obvious by Bielekova in view of Enyindah-Asonye would successfully result in obtaining information regarding the MS status of patients.
Therefore, claims 1, 171-173, 175, 178-179, and 183 are rendered obvious by Bielekova in view of Enyindah-Asonye and Huang and are rejected under 35 U.S.C. 103.
The Supreme Court has acknowledged:
When a work is available in one field of endeavor, design incentives and other market forces can prompt variations of it, either in the same field or a different one. If a person of ordinary skill can implement a predictable variation…103 likely bars its patentability…if a technique has been used to improve one device, and a person of ordinary skill in the art would recognize that it would improve similar devices in the same way, using the technique is obvious unless its actual application is beyond that person’s skill. A court must ask whether the improvement is more than the predictable use of prior-art elements according to their established functions……the combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results (see KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 U.S. 2007) (emphasis added).
From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1, 171-173, 175, 178-179, and 183 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of U.S. Patent No. 12474336 or over claims 1-15 of U.S. Patent No. 12474336 in view of Huang et al., Proc. Nat’l. Acad. Sci. USA 117(23): 12952-12960 (2020; published 09 June 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘336 recite a biomarker set that contains more biomarkers in addition to the instantly elected biomarker set. The claims of ‘336 recite all of the additional limitations of the cited instant claims except for the determination of particular reference scores, which are obvious over ‘336 in view of the teachings of Huang as discussed above. As such, the instant claims are ‘anticipated’ by the cited claims of ‘336 or ‘rendered obvious’ by the cited claims of ‘336 in view of Huang and are rejected on the ground of nonstatutory double patenting.
Claims 1, 171-173, 175, 178-179, and 183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-20 of copending Application No. 19/364861 or over claims 1-20 of copending Application No. 19/364861 in view of Huang et al., Proc. Nat’l. Acad. Sci. USA 117(23): 12952-12960 (2020; published 09 June 2020). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘861 recite a biomarker set that contains more biomarkers in addition to the instantly elected biomarker set. The claims of ‘861 recite all of the additional limitations of the cited instant claims except for the determination of particular reference scores, which are obvious over ‘861 in view of the teachings of Huang as discussed above. As such, the instant claims are ‘anticipated’ by the cited claims of ‘861 or ‘rendered obvious’ by the cited claims of ‘861 in view of Huang and are provisionally rejected on the ground of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Claims 1, 171-173, 175, 178-179, and 183 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-14, 17, 20, and 24-25 of copending Application No. 19/190530 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of ‘530 recite biomarker sets that contain more biomarkers in addition to the instantly elected biomarker set. As such, the instant claims are ‘anticipated’ by the cited claims of ‘530 and are provisionally rejected on the ground of nonstatutory double patenting.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Erin M. Bowers, whose telephone number is (571)272-2897. The examiner can normally be reached Monday-Friday, 7:30-5:00.
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/Erin M. Bowers/Primary Examiner, Art Unit 1653 05/27/2026
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