DETAILED CORRESPONDENCE
Status of the Application
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claims 90, 92-95, 97-111 are pending in this application.
Applicant’s amendment to the claims filed 12/04/2024 is acknowledged. This listing of the claims replaces all prior versions and listings of the claims.
Election
Applicant’s election with traverse of
Species of Group A) the polypeptide Ribosomal protein S6 kinase alpha-5, and
Species of Group B) the metabolite creatinine
in the reply filed 12/04/2024 is acknowledged. The traversal is on the grounds that there is no connection between XRCC1 disclosed by Caldecott et al. (DNA Repair, 2003, 2:955; cited on the Form PTO-892 mailed 10/10/2024) and multiple sclerosis, nor between creatine disclosed by Brosnan et al. (Ann Rev Nutrition, 2007, 27:241; cited on the Form PTO-892 mailed 10/10/2024) and multiple sclerosis. Applicant’s arguments are considered and not found convincing, as the shared same or corresponding technical feature among the species of Group A is considered to be a polypeptide, and in view of the disclosure of polypeptides by Caldecott, the shared same or corresponding technical feature is not a special technical feature as it does not make a contribution over the prior art, therefore the species of Group A lack unity of invention. Furthermore, the shared same or corresponding technical feature among the species of Group B is considered to be a metabolite, and in view of the disclosure of metabolites by Brosnan, the shared same or corresponding technical feature is not a special technical feature as it does not make a contribution over the prior art, therefore the species of Group B lack unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Claim 111 is withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made with traverse in the reply filed on 12/04/2024.
Claims 90, 92-95, and 97-110 are being examined on the merits only to the extent they read on the elected subject matter.
Priority
The instant application is a national stage filing under 35 U.S.C. 371 of international application PCT/GB2020/051615 filed 07/06/2020, which claims foreign priority to British Application No. 1909619.7 filed 07/04/2019.
Information Disclosure Statement
The Information Disclosure Statement (IDS) submitted on 01/04/2022 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the IDS has been considered by the examiner.
Objections to Specification
The disclosure is objected to because of the following informalities.
The use of the terms BD VACUTAINER, SOMASCAN, SOMAMER and TOPSPIN which are trade names or marks used in commerce, have been noted in this application on pages 112-114. The terms should be accompanied by the generic terminology; furthermore the terms should be capitalized wherever they appears or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the terms.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
Appropriate correction is required.
Objections to Drawings
The drawings are objected to because the multiple views of Figure 1 should be labeled as FIG. 1A and FIG. 2A with the corresponding descriptions of each panel disclosed in the specification.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claim 90 is objected to as including periods within the body of the claim in the recitation of claim alternatives “i.”, “ii.”, “iii.” and “iv.”. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. The applicant may consider an amendment to replace “i.”, “ii.”, “iii.” and “iv.” with “(i)”, “(ii)”, “(iii)”, and “(iv)”, respectively throughout the claim where they appear.
Claim 110 is objected to for reciting “a.” and “b.” to delineate alternatives and for including a period at the end of alternative b. According to MPEP 608.01(m), “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations. See Fressola v. Manbeck, 36 USPQ2d 1211 (D.D.C. 1995)”. The applicant may consider an amendment to replace “a.” and “b.” with “(a)” and “(b)”, respectively.
Claims 90 and 110 are objected to for containing multiple substeps of step d., wherein multiple substeps are each labeled “i.”, “ii.”, “iii.” and “iv.” In the interest of improving claim form, Applicant should consider an amendment to recite single steps labeled (d)(i)-(d)(viii).
Claim Rejections - 35 USC § 112(b)
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.
Claims 90, 92-95, 97-99 and 100-111 are rejected under 35 U.S.C. 112(b) as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
Claim 90 (claims 92-95, 97-99 and 111 dependent therefrom) is rejected for the recitation of the phrase “a subject who has CIS and is a rapid convertor to CDMS”, as the term "rapid" in is a relative term which renders the claim indefinite. Regarding the term, the instant specification discloses on p 8 that a “rapid converter” may be a subject who converts within 10 years of CIS occurring, while in one embodiment it is a subject who converts within 5 years of a CIS occurring, and preferably is a subject who converts from within 4 years of a CIS occurring. As such, the term "rapid" is not clearly defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claim 90 (claims 92-95, 97-99 and 111 dependent therefrom) is rejected for the recitation of the phrase “a subject who has CIS and is a slow convertor to CDMS”, as the term "slow" in is a relative term which renders the claim indefinite. Regarding the term, the instant specification discloses on p 9 that a “slow converter” may be a subject who converts more than 10 years from CIS occurring, in one embodiment it is a subject who converts more than 5 years from a CIS occurring, and preferably is a subject who converts more than 4 years from a CIS occurring. As such, the term "slow" is not clearly defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention.
Claims 93 and 104 are rejected for the recitation of the phrases “wherein the concentration of the one or more polypeptides is assayed” and “using the technique selected from: … northern blot, RT-PCR, RNA sequencing, transcriptomics”, as it is unclear how the concentration of protein is assayed usi.ng techniques for measuring concentration of nucleic acids
Claim 100 (claims 101-110 dependent therefrom) is indefinite for the recitation of the phrases
“determining that the subject will convert when … the assayed concentrations … is decreased when compared to … a non-convertor reference standard” in step (d)(ii),
“determining that the subject will convert when … the assayed concentrations … is decreased when compared to … a converter reference standard” in step (d)(iv),
“determining that the subject will not convert when … the assayed concentrations … is increased when compared to … a non-convertor reference standard” in step (d)(ii)(alternate), and
“determining that the subject will not convert when … the assayed concentrations … is increased when compared to … a convertor reference standard” in step (d)(iv)(alternate). It is unclear how observing the same relative result compared to opposite reference standards can produce the same conclusion. Put another way, it is unclear how a convertor is determined by observing a decrease in target molecule concentration compared to both a convertor and a non-convertor standard, as the two standards are interpreted to be synonymous with positive and negative controls for carrying out the method. Similarly, it is unclear how a convertor is determined by observing and increase in target molecule concentration compared to both a convertor and a non-convertor standard, as the two standards are interpreted to be synonymous with positive and negative controls for carrying out the method.
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 90, 92-95 and 98-109 are rejected under 35 U.S.C. 101 because the claimed invention is directed to an abstract idea without significantly more. The claims below were evaluated using “Subject Matter Eligibility Test for Products and Processes” as shown in MPEP 2016 III.
Claims 90, 92-95 and 98-99:
Patent Eligibility Analysis Step 1: The claim is drawn to a process (method) which is one of the four statutory categories.
Patent Eligibility Analysis Step 2A Prong 1: The claims are recite the abstract ideas of “measuring a concentration” in recited in step (b), “comparing the measured concentration” in step (c), and “determining that the subject will convert from CIS to CMDS” and “determining that the subject will not convert from CIS to CDMS” recited in step (d) of independent claim 90. In the broadest reasonable interpretation of the claim, “measuring” encompasses the mental action of counting, “comparing” encompasses the mental action of analyzing at least two data points, and “determining” encompasses the mental action of interpreting data to arrive at a conclusion. Accordingly, claims 90, 92-95 and 98-99 recite judicial exceptions.
Patent Eligibility Analysis Step 2A Prong 2: Claim 90 recites the additional element of “obtaining a biofluid sample” in step (a). However, the additional element encompasses data gathering needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract ideas, or how the abstract ideas are performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
Claim 99 recites the additional element of recording the output of steps (b), (c) and (d) on a data-storage medium. However, under the broadest reasonable interpretation, “recording the output of steps” is drawn to writing down data values on paper, which is considered a mental activity, and therefore claim 99 recites an additional judicial exception. Alternatively, the additional element is considered to encompass data gathering and data outputting, which do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into practical application (MPEP 2106.05(g)).
There are no additional elements recited in claims 92-95 and 98, 100-109 beyond the judicial exception.
Patent Eligibility Analysis Step 2B: Achiron et al. (US 2010/0112568A1; cited on the IDS submitted 01/04/2022), Weiner et al. (WO 2013/055865 A1; cited on the IDS submitted 01/04/2022) and Powers et al. (J Proteome Res, 2016, 15:659; cited on the attached Form PTO-892) all relate to methods of biomarker detection from samples derived from MS patients or patients with clinically isolated syndrome comprising blood samples [Weiner, regarding testing of monocytes in blood, p 19, para 2; Achiron, regarding the testing of blood cells derived from patient’s blood, para 0026] or urine samples [Powers, abstract]. Additionally, while the methods of Achiron, Weiner and Powers do not explicitly recite the recording of output of the steps on a data-storage medium, the output of these steps is considered inherently to be recorded in order to carry out the respective disclosed methods, specifically in view of the multivariate analysis of Powers [p 660, col 2, final paragraph] and statistical analysis of Weiner [p 20, beginning col 3]. In view of Achiron, Weiner and Powers, the additional element of “obtaining a biofluid sample” in step (a) of claim 90 and “recording the output of steps” in claim 99 are considered to be well-understood, routine and conventional activities previously known to the industry (MPEP 2106.05(d)), and therefore the judicial exception is recited without additional limitations amounting to significantly more than the exception. All of the signified additional elements to the judicial exception are considered to be required data collection steps of the judicial exception that are well-understood, routine and conventional, and, therefore, do not amount to significantly more than the judicial exception that is claimed.
Claims 100-109:
Patent Eligibility Analysis Step 1: The claim is drawn to a process (method) which is one of the four statutory categories.
Patent Eligibility Analysis Step 2A Prong 1: The claims recite the abstract ideas of “assaying the biofluid sample for a concentration” in step (b), “comparing the assayed concentrations” in step (c), and “determining that the subject will convert from CIS to CMDS” and “determining that the subject will not convert from CIS to CDMS” in step (d) of independent claim 100. In the broadest reasonable interpretation, “assaying the biofluid sample for a concentration” encompasses the mental action of measuring or counting the amount of a component of a sample, “comparing” encompasses the mental action of analyzing at least two data points, and “determining” encompasses the mental action of interpreting data to arrive at a conclusion. Accordingly, claims 100-109 recite judicial exceptions.
Patent Eligibility Analysis Step 2A Prong 2: Claim 100 recites the additional element of “obtaining a biofluid sample” in step (a). However, the additional element encompasses data gathering needed to carry out the abstract idea. Data gathering does not impose any meaningful limitation on the abstract ideas, or how the abstract ideas are performed. Data gathering steps are not sufficient to integrate an abstract idea into a practical application (MPEP 2106.05(g)).
Claim 108 recites the additional element of recording the output of steps (b), (c) and (d) on a data-storage medium. However, under the broadest reasonable interpretation, “recording the output of steps” encompasses writing down data values on paper, which is considered a mental activity, and therefore claim 108 recites an additional judicial exception. Alternatively, the additional element encompasses data gathering and data outputting, which do not impose any meaningful limitation on the judicial exceptions, or on how the judicial exceptions are performed. Data gathering and outputting steps are not sufficient to integrate judicial exceptions into practical application (MPEP 2106.05(g)).
There are no additional elements recited in claims 101-107 and 109 beyond the judicial exception.
Patent Eligibility Analysis Step 2B: Achiron et al. (US 2010/0112568A1; cited on the IDS submitted 01/04/2022), Weiner et al. (WO 2013/055865 A1; cited on the IDS submitted 01/04/2022) and Powers et al. (J Proteome Res, 2016, 15:659; cited on the attached Form PTO-892) all relate to methods of biomarker detection from samples derived from MS patients or patients with clinically isolated syndrome comprising blood samples [Weiner, regarding testing of monocytes in blood, p 19, para 2; Achiron, regarding the testing of blood cells derived from patient’s blood, para 0026] or urine samples [Powers, abstract]. Additionally, while the methods of Achiron, Weiner and Powers do not explicitly recite the recording of output of the steps on a data-storage medium, the output of these steps is considered inherently to be recorded in order to carry out the respective disclosed methods, specifically in view of the multivariate analysis of Powers [p 660, col 2, final paragraph] and statistical analysis of Weiner [p 20, beginning col 3]. In view of Achiron, Weiner and Powers, the additional element of “obtaining a biofluid sample” in step (a) of claim 100 and “recording the output of steps” in claim 108 are considered to be well-understood, routine and conventional activities previously known to the industry (MPEP 2106.05(d)), and therefore the judicial exception is recited without additional limitations amounting to significantly more than the exception. All of the signified additional elements to the judicial exception are considered to be required data collection steps of the judicial exception that are well-understood, routine and conventional, and, therefore, do not amount to significantly more than the judicial exception that is claimed.
As the instant claims recite judicial exceptions that are not integrated into practical application, and no elements that amount to significantly more than the judicial exception as recited, the claims were found not to be drawn to eligible subject matter under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 90, 92-93, 95, 97-101, 103-104, and 106-109 are rejected under 35 U.S.C. 103 as being unpatentable over Achiron et al. (US 2010/0112568A1; cited on the IDS submitted 01/04/2022; herein referred to as Achiron) in view of Weiner et al. (WO 2013/055865 A1; cited on the IDS submitted 01/04/2022; herein referred to as Weiner).
Claim 90 is drawn (in relevant part, in view of the species election) to a method for determining conversion of a subject from clinically isolated syndrome (CIS) to clinically definite multiple sclerosis (CDMS), the method comprising:
obtaining a biofluid sample derived from a subject having, or suspected of having, CIS;
measuring a concentration of:
i. one or more polypeptides in the sample; and/or
ii. one or more metabolites in the sample;
comparing the measured concentration with the concentration of the same one or more polypeptides and/or metabolites, respectively, in a reference standard; and
determining that the subject will convert from CIS to CDMS when:
ii. the measured concentration of one or more polypeptides selected from: Ribosomal protein S6 kinase alpha-5 is decreased when compared to the reference standard when the reference standard is a non-convertor reference standard, or
iv. the measured concentration of one or more polypeptides selected from: Ribosomal protein S6 kinase alpha-5 is increased when compared to the reference standard when the reference standard is a convertor reference standard;
and/or determining that the subject will not convert from CIS to CDMS when:
ii. the measured concentration of one or more metabolites selected from: creatinine is increased or the same when compared to the reference standard when the reference standard is a non-convertor reference standard; or
iv. the measured concentration of one or more metabolites selected from: creatinine is increased when compared to the reference standard when the reference standard is a convertor reference standard; and
wherein the non-convertor reference standard corresponds to a subject who has CIS but is a slow convertor to CDMS or does not convert to CDMS, or that has CIS but does not have multiple sclerosis (MS); or
wherein the convertor reference standard corresponds to a subject who has CIS and is a rapid convertor to CDMS or that has MS.
The instant specification does not specifically define the term “CIS”, but gives examples that it is “an initial neurological attack” [p 1] and “may refer to a first episode of neurologic symptoms that lasts for at least 24 hours and that is caused by inflammation and/or demyelination in the brain of the subject” [p 3].
The instant specification does not clearly define the terms “rapid convertor” and “slow convertor”, but provides the following examples:
“A ‘rapid convertor’ (used synonymously with ‘fast convertor’ herein) may be a subject who converts from CIS to CDMS within 10 years of CIS occurring. In one embodiment a ‘rapid convertor’ is a subject who converts from CIS to CDMS within 5 years of CIS occurring. Preferably, a ‘rapid convertor’ is a subject who converts from CIS to CDMS within 4 years of CIS occurring” [p 8-9],
and
“A ‘slow convertor’ may be a subject who converts from CIS to CDMS in more than 10 years5 of CIS occurring. In one embodiment a ‘slow convertor’ is a subject who converts from CIS to CDMS in more than 5 years of CIS occurring. Preferably, a ‘slow convertor’ is a subject who converts from CIS to CDMS in more than 4 years of CIS occurring” [p 9].
In view of the specification, and for the sake of the examination, the term “rapid convertor” is being interpreted as a subject who converts from CIS to CDMS within 10 years of CIS occurring, and the term “slow convertor” is being interpreted as a subject who converts from CIS to CDMS more than 10 years from CIS occurring.
Achiron relates to methods for diagnosis of MS in probable MS subjects [title].
Regarding claims 90, 92 and 98, Achiron discloses the differential expression of markers in subjects diagnosed with probable MS which further develop the definite diagnosis of MS [para 0001], and describes a method for identifying a patient with CIS at high risk for developing MS by detecting the level of expression of a marker gene and comparing the level of expression to a control [claim 1], which corresponds to the limitations in steps a., and d., as determining the expression of a marker gene is interpreted to encompass obtaining a biofluid sample from a patient.
Achiron does not teach measuring the concentrations of the Ribosomal protein S6 kinase alpha-5 (RPS6KA5) or creatinine, or the comparison to non-convertor and convertor reference standards.
Weiner relates to neurodegenerative disorders (NDD) [title] and discloses methods for diagnosing NDD in a subject, identifying subject at risk of developing NDD, wherein the NDD is MS [abstract].
Regarding claims 90, 92 and 98, Weiner discloses a method for diagnosing and identifying subjects at risk for NDD by determining the level of inflammatory markers on monocytes or in CSF [abstract], wherein RPS6KA5 is shown to be an inflammatory marker that is decreased in monocytes from patients having NDD relative to healthy controls [Table 20], which corresponds to the limitations of measuring concentrations of RPSKA5 and comparing them to a control, which are interpreted to correspond to the limitations in steps b., c. and d of claim 90. Weiner further discloses that healthy controls come from a subject that does not present with two or more symptoms of a neurodegenerative disorder, a subject that has not been diagnosed with a neurodegenerative disorder, and/or a subject that has no family history of neurodegenerative disease [p 17, para 2], which is considered to encompass the non-convertor reference standard of a subject that has CIS but does not have multiple sclerosis (MS) as recited in the claims.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine Achiron and Weiner to modify the method of Achiron by detecting the polypeptide RPS6KA5, as taught by Weiner, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the method of Achiron by detecting the polypeptide RPS6KA5, because Weiner teaches that methods for identifying subject at risk of developing MS comprising detecting differential levels of the polypeptide RPS6KA5. One of ordinary skill in the art would have had a reasonable expectation of success because both Achiron and Weiner relate to methods for identifying and diagnosing MS in probable MS subjects.
Regarding claim 93, Achiron discloses the use of Northern blot analysis and RT-PCR to characterize expression [para 0063].
Regarding claim 95, Achiron discloses the testing of samples comprising blood cells [claim 17], which is considered to correspond to the biofluid sample being blood.
Regarding claim 97, Achiron discloses upon the determination that one might develop definite MS, the subject can be treated with suitable therapeutics to prevent deterioration of clinical symptoms and can increase the chance of achieving cure and remission of symptoms [para 0079], which is interpreted to correspond to the delay of conversion.
Regarding claim 99, Achiron and Weiner discloses the combined method described in the rejections of claim 90 above, which do not explicitly recite the recording of output of the steps on a data-storage medium. However, as the output of these steps is considered inherently to be recorded in order to carry out the disclosed methods, under the broadest reasonable interpretation the output of these steps is recorded by hand on paper, wherein paper is considered to be encompassed by a data-storage medium. As such, the combined method of Achiron and Weiner satisfies the claim limitations. Considering an alternative interpretation that data-storage medium is intended to mean a computer-readable medium, according to MPEP 2144.04.III, it is obvious to automate a manual activity, wherein broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.
Regarding claim 100 (and claims 101, 103-104, and 106-110 dependent therefrom), in view of the indefiniteness of the claim as recited above, and for the sake of compact prosecution, the claim is being examined based on the interpretation that a subject will convert to CDMS when the measured concentration of polypeptide or metabolite is decreased compared to a non-converter reference standard, and will not convert to CDMS when said concentrations are increased compared to a converter reference standard.
Regarding claims 100, 103 and 107, Achiron discloses the differential expression of markers in subjects diagnosed with probable MS which further develop the definite diagnosis of MS [para 0001], and describes a method for identifying a patient with CIS at high risk for developing MS by detecting the level of expression of a marker gene and comparing the level of expression to a control [claim 1], which corresponds to the limitations in steps a., and d., as determining the expression of a marker gene is interpreted to encompass obtaining a biofluid sample from a patient. Weiner discloses a method for diagnosing and identifying subjects at risk for NDD by determining the level of inflammatory markers on monocytes or in CSF [abstract], wherein RPS6KA5 is shown to be an inflammatory marker that is decreased in monocytes from patients having NDD relative to healthy controls [Table 20], which corresponds to the limitations of measuring concentrations of RPSKA5 and comparing them to a control, which are interpreted to correspond to the limitations in steps b., c. and d. of claim 100. Weiner further discloses that healthy controls come from a subject that does not present with two or more symptoms of a neurodegenerative disorder, a subject that has not been diagnosed with a neurodegenerative disorder, and/or a subject that has no family history of neurodegenerative disease [p 17, para 2], which is considered to encompass the non-convertor reference standard of a subject that has CIS but does not have multiple sclerosis (MS) as recited in the claims.
It would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to combine Achiron and Weiner to modify the method of Achiron by detecting the polypeptide RPS6KA5, as taught by Weiner, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the method of Achiron by detecting the polypeptide RPS6KA5, because Weiner teaches that methods for identifying subject at risk of developing MS comprising detecting differential levels of the polypeptide RPS6KA5. One of ordinary skill in the art would have had a reasonable expectation of success because both Achiron and Weiner relate to methods for identifying and diagnosing MS in probable MS subjects.
Regarding claim 101, Achiron discloses the method wherein the differential expression of a marker indicates a high probability of the subject to develop definite MS within a period of about 2 years [para 0068].
Regarding claim 104, Achiron discloses the use of Northern blot analysis and RT-PCR to characterize expression [para 0063].
Regarding claim 106, Achiron discloses the testing of samples comprising blood cells [claim 17], which is considered to correspond to the biofluid sample being blood.
Regarding claim 108, Achiron and Weiner discloses the combined method described in the rejections of claim 100 above, which do not explicitly recite the recording of output of the steps on a data-storage medium. However, as the output of these steps is considered inherently to be recorded in order to carry out the disclosed methods, under the broadest reasonable interpretation the output of these steps is recorded by hand on paper, wherein paper is considered to be encompassed by a data-storage medium. As such, the combined method of Achiron and Weiner satisfies the claim limitations. Considering an alternative interpretation that data-storage medium is intended to mean a computer-readable medium, according to MPEP 2144.04.III, it is obvious to automate a manual activity, wherein broadly providing an automatic or mechanical means to replace a manual activity which accomplished the same result is not sufficient to distinguish over the prior art.
Regarding claim 109, Achiron discloses upon the determination that one might develop definite MS, the subject can be treated with suitable therapeutics to prevent deterioration of clinical symptoms and can increase the chance of achieving cure and remission of symptoms [para 0079], which is interpreted to correspond to the delay of conversion.
Therefore, the invention of claims 90, 92-93, 95, 97-101, 103-104, and 106-109 would have been obvious to one of ordinary skill in the art before the effective filing date.
Claims 94, 102, 105 and 110 are rejected under 35 U.S.C. 103 as being unpatentable over Achiron and Weiner as applied to claims 90, 92-93, 95, 97-101, 103-104, and 106-109 above, and further in view of Powers et al. (J Proteome Res, 2016, 15:659; reference is made to both the article and the Supplemental Information section, both cited on the attached Form PTO-892; herein referred to as Powers).
Regarding claims 102, 105 and 110 dependent from claim 100 above, in view of the indefiniteness of claim 100 as recited above, and for the sake of compact prosecution, the claims are being examined based on the interpretation that a subject will convert to CDMS when the measured concentration of polypeptide or metabolite is decreased compared to a non-converter reference standard, and will not convert to CDMS when said concentrations are increased compared to a converter reference standard.
Claim 94 is drawn to the method of claim 90, wherein the concentration of the one or more metabolites is assayed using a technique selected from: Nuclear Magnetic Resonance (NMR) spectroscopy, mass spectrometry, HPLC-UV, and infrared spectrometry.
The teachings of Achiron and Weiner as applied to claims 90, 92-93, 95, 97-101, 103-104, and 106-109 are discussed above. These references do not teach the identification of metabolites related to MS patients nor methods of assaying metabolites.
Powers relates to the urinary metabolic signature for MS [title], and discloses that clinical diagnoses routinely rely on urine samples and represents an under-investigated source of biomarkers for MS [abstract], as the analysis of urine samples to obtain a metabolic profile has the advantages of being a rapid, easy, inexpensive and noninvasive sample collection procedure [p 659, col 2, para 2].
Regarding claims 94, 102 and 105, Powers discloses a method comprising the use of NMR on urine samples [p 660, col 2, para 3] to identify metabolites from MS patients to compare to healthy controls [p 661, col 1, para 2], wherein creatinine was one of 6 metabolites detected that discriminate between healthy controls and MS patients [p 662, col 2, para 1], which are identified as decreased in MS patients compared to controls [Table S2 and Figure S2].
In view of Powers, it would have been prima facie obvious for one of ordinary skill in the art before the effective filing date of the claimed invention to modify the combined method of Achiron and Weiner by additionally detecting creatinine levels, as taught by Powers, to arrive at the claimed invention. One of ordinary skill in the art would have been motivated to modify the combined method of Achiron and Weiner by additionally detecting creatinine levels, because Powers teaches clinical diagnoses routinely rely on urine samples and represents an under-investigated source of biomarkers for MS that has many logistical advantages, and shows creatinine is a metabolite that discriminates between healthy controls and MS patients. One of ordinary skill in the art would have had a reasonable expectation of success because Achiron, Weiner and Powers relate to methods for identifying biomarkers to distinguish probable MS subjects.
Further regarding claim 102, Achiron and Weiner disclose methods of identifying biomarkers for identifying and diagnosing MS in probable MS subjects as discussed in the rejections of claims 90 and 110 above, and Powers discloses a method of detecting creatinine that distinguishes samples from MS patients from non-MS patients [p 662, col 2, para 1]. Therefore, the detection of RPS6KA5 and the detection of creatinine are both art recognized equivalents for the same purpose of identifying biomarkers that differentiate MS patients from controls. According to MPEP 2144.06, it is prima facie obvious to combine equivalents known for the same purpose.
Regarding claim 110, Powers discloses interferon β-b1 as a therapeutic for the treatment of patients with MS [p 660, col 2, para 1], indicating this as a therapeutic for the treatment of MS.
Therefore, the invention of claims 94, 102, 105 and 110 would have been obvious to one of ordinary skill in the art before the effective filing date.
Conclusion
Status of the Application:
Claims 90, 92-95, 97-111 are pending.
Claim 111 is withdrawn.
Claims 90, 92-95, 97-110 are rejected.
No claim is in condition for allowance.
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/JOSEPH R SPANGLER/
Examiner
Art Unit 1656
/David Steadman/Primary Examiner, Art Unit 1656
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