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 .
Status of the claims
The Preliminary Amendment filed 01/16/26 is acknowledged and has been entered. Claims 1-3, 5, 7, 10-12, 14 and 16 have been amended. Claims 9 and 18-27 have been canceled. Accordingly, claims 1-8 and 10-17 are pending and under examination.
Information Disclosure Statement
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Specification
The specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant’s cooperation is requested in correcting any errors of which applicant may become aware in the specification.
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.
Written Description
Claims 1-8 and 10-17 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 written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The instant claims are directed to methods for determining the level of expression of two or more biomarkers for diagnosing relapsing-remitting multiple sclerosis (RRMS) and treating or monitoring treatment by determining the level in any and all biological samples from any and all subjects. The limitation 'subject’ represents a genus and encompasses human and non-human including mouse, monkey, dog, rat, pig, insects, kangaroo, horse, canine and snake to name a few. The limitation ‘biological sample’ represents a genus and encompasses tears, semen, liver, urine, kidney, brain, peritoneal fluid, sputum, synovial fluid, lung tissues or vomit. However, there is inadequate written description in the instant specification for a method of such broad scope as claimed currently.
In order to fulfill the written description requirements set forth under 35 U.S.C § 112, first paragraph, the specification must describe at least a substantial number of the members of the claimed genus, or alternatively describe a representative member of the claimed genus, which shares a particularly defining feature common to at least a substantial number of the members of the claimed genus, each member correlated with the requisite function, which would enable the skilled artisan to immediately recognize and distinguish its members from others, so as to reasonably convey to the skilled artisan that Applicants have possession the claimed invention. Applicants have not described and established structure-function correlation for a representative number of species within the broad genus of at least the recited ‘subject’, ‘biological sample’ such that the specification might reasonably convey to the skilled artisan that Applicants had possession of the full scope of the claimed invention at the time the application was filed.
The purpose of the written description requirement is ‘to ensure that the inventor had possession, as of the filing date of the application relied on, of the specific subject matter later claimed by him.’ In re Edwards, 568 F.2d 1349, 1351-52, 196 USPQ 465, 467 (CCPA 1978). Possession may not be shown by merely describing how to obtain possession of members of the claimed genus or how to identify their common structural features. See University of Rochester, 358 F.3d at 927, 69 USPQ2d at 1895. A ‘representative number of species’ means that the species which are adequately described are representative of the entire genus. When there is substantial structural variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
A review of the instant specification indicates the following. The specification on pages 5-6, para’s 0012-0018 discloses the determination of serum proteins in RRMS patients (which appear to be human) and healthy controls. The specification on page 7, para 0023 discloses measuring levels of blood proteins in RRMS patient cohorts (which appear to be human). The specification on page 10, para 0034 discloses the measurement of proteins in blood from patients (humans). The specification on page 11, para 0038 discloses measuring serum proteins in RRMS patients. The specification on pages 14-15, para’s 0045-0047 discloses the measurement of blood proteins in MS relapse patients. The examples in the specification all appear to be directed to patients that are human and the measurement of lowered levels of the recited biomarkers in either, blood, serum or plasma from patients with RRMS. The specification does not provide data, testing or examples with a showing that any all and all biological samples from any and all patients provide the recited biomarkers at levels which can be specifically correlated with RRMS. Also, Torzewski et al, (Hindawl Publishing Corporation, Mediators of Inflammation, Vol 2014, Articles ID 683598, pages 1-7) teaches for example that CRP (biomarker) is an acute phase reactant in humans but not an acute phase reactant in a mouse (e.g. page 1). Van Der Vekens et al., (Cardiovascular Endocrinology, 2013, Vol 2, No. 4,pages 67-76) teaches that markers between human and equine show important species differences, which can be explained by variations in physiology or pathophysiology and also teaches pathological differences in the species (e.g. abstract).
The only examples utilized in the specification appears to be limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS. The specification does not disclose that the recited biomarkers which appear in blood, serum or plasma also appear in samples such as stool, tears lung, brain, sputum, plural fluid etc. or that such proteins would be expected to be shed, excreted into or found in these samples and correlated with RRMS. As stated supra the specification appears to be limited to limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS.
The specification also fails to provide for a correlation of the recited biomarkers in all patients such as dogs, cats, cows, monkey, horse, rabbit squirrel and mice (as shown supra by Torzewski and Van Der Vekens different species of mammal have different expression of biomarkers and do not correlate to the same condition/disease) The specification also fails to provide that the recited biomarkers exist in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of these biomarkers exist in such patients with RRMS. Further, it is not well known in the art that these samples provide for the recited biomarkers and that a correlation exists between such biomarkers in the samples with RRMS. The examples in the specification appear to be limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS. The purpose of the ‘written description; requirement is broader than to merely explain how to ‘make and use’, Applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention.
It must be noted that "[t]he applicant must . . . convey to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention." Vas-Cath, Inc. v. Mahurkar, 935 F.2d 1555, 1563-64 (Fed. Cir.1991). The invention, is for purposes of the ‘written description’ inquiry, whatever is now claimed.” See page 1117. The specification does not describe the claimed embodiments in sufficient detail to convey to a person skilled in the art that Applicants were in possession of the full scope of the claimed invention at the time of filing. The Written Description Guidelines state: There is an inverse correlation between the level of predictability in the art and the amount of disclosure necessary to satisfy the written description requirement. For example, if there is a well-established correlation between the structure and function in the art, one skilled in the art will be able to reasonably predict the complete structure of the claimed invention from its function. Furthermore, the written description provision of 35 U.S.C § 112 is severable from its enablement provision; and adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. The Guidelines for Examination of Patent Applications Under the 35 U.S.C. 112, paragraph 1, ‘Written Description’ Requirement (66 FIR 1099-1111, January 5,2001) state, ‘[p]ossession may be shown in a variety of ways including description of an actual reduction to practice, or by showing that the invention was 'ready for patenting' such as by disclosure of drawings or structural chemical formulas that show that the invention was complete, or by describing distinguishing identifying characteristics sufficient to show that the Applicant was in possession of the claimed invention’ (Id. at 1104). Moreover, because the claims encompass a genus of variant species, an adequate written description of the claimed invention must include sufficient description of at least a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant identifying characteristics sufficient to show that Applicant was in possession of the claimed genus. Factual evidence of an actual reduction to practice has not been disclosed in the instant specification, nor has Applicant shown the invention was ‘ready for patenting’. The Guidelines further state, ‘[f]or inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus' (Id. at 1106). For inventions in emerging and unpredictable technologies, or for inventions characterized by factors not reasonably predictable which are known to one of ordinary skill in the art, more evidence is required to show possession. Instant claims are viewed as not meeting the written description provision of 35 U.S.C § 112, first paragraph. The specification fails to disclose the detection of the recited biomarkers in any and all biological samples from any and all patients wherein lower levels of the biomarkers are directly correlated with RRMS.
Scope of Enablement
Claims 1-8 and 10-17 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for analyzing RRMS in a human subject, comprising detecting a first level of expression for of two or more biomarkers selected from urokinase plasminogen activator (uPA), kallikrein-8 (hK8), kallikrein-11 (hK11), or desmoglein- 3 (DSG3) in a first blood, serum or plasma sample of the subject; (b) comparing the first level of expression of the two or more biomarkers to a second level of expression of the two or more biomarkers in a second sample of the same type as the first sample, the second sample being from a subject or a population of subjects in remission from RRMS; (c) diagnosing the subject in (a) as undergoing relapse if the first level of expression of the two or more biomarkers is lower than the second level of expression; and (d) administering a therapeutically effective amount of a treatment for RRMS to the subject if the subject is diagnosed as undergoing relapse in (c). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
Enablement requires that the specification teach those in the art to make and use the invention without undue experimentation. The factors that must be considered in determining undue experimentation are set forth in In re Wands USPTQ2d 14000. Factors to be considered in determining whether a disclosure would require undue experimentation include (1) the nature of the invention, (2) the state of the prior art, (3) the predictability or lack thereof in the art, (4) the amount of direction or guidance present, (5) the presence or absence of working examples, (6) the quantity of experimentation necessary, (7) the relative skill of those in the art, and (8) the breadth of the claims.
The instant claims are directed to methods for determining the level of expression of two or more biomarkers for diagnosing relapsing-remitting multiple sclerosis (RRMS) and treating or monitoring treatment by determining the level in any and all biological samples from any and all subjects.
One cannot extrapolate the teaching of the specification to the enablement of the claims because other than detecting B2MG in a human serum or plasma sample and comparing to a control survivor patient suffering from cardiogenic shock and determining an increased level as compared to the control as indicating mortality risk in the patient.
A review of the instant specification indicates the following. The specification on pages 5-6, para’s 0012-0018 discloses the determination of serum proteins in RRMS patients (which appear to be human) and healthy controls. The specification on page 7, para 0023 discloses measuring levels of blood proteins in RRMS patient cohorts (which appear to be human). The specification on page 10, para 0034 discloses the measurement of proteins in blood from patients (humans). The specification on page 11, para 0038 discloses measuring serum proteins in RRMS patients. The specification on pages 14-15, para’s 0045-0047 discloses the measurement of blood proteins in MS relapse patients. The examples in the specification all appear to be directed to patients that are human and the measurement of lowered levels of the recited biomarkers in either, blood, serum or plasma from patients with RRMS. The specification does not provide data, testing or examples with a showing that any all and all biological samples from any and all patients provide the recited biomarkers at levels which can be specifically correlated with RRMS. Also, Torzewski et al, (Hindawl Publishing Corporation, Mediators of Inflammation, Vol 2014, Articles ID 683598, pages 1-7) teaches for example that CRP (biomarker) is an acute phase reactant in humans but not an acute phase reactant in a mouse (e.g. page 1). Van Der Vekens et al., (Cardiovascular Endocrinology, 2013, Vol 2, No. 4,pages 67-76) teaches that markers between human and equine show important species differences, which can be explained by variations in physiology or pathophysiology and also teaches pathological differences in the species (e.g. abstract).
The only examples utilized in the specification appears to be limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS. The specification does not disclose that the recited biomarkers which appear in blood, serum or plasma also appear in samples such as stool, tears lung, brain, sputum, plural fluid etc. or that such proteins would be expected to be shed, excreted into or found in these samples and correlated with RRMS. As stated supra the specification appears to be limited to limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS.
The specification also fails to provide for a correlation of the recited biomarkers in all patients such as dogs, cats, cows, monkey, horse, rabbit squirrel and mice (as shown supra by Torzewski and Van Der Vekens different species of mammal have different expression of biomarkers and do not correlate to the same condition/disease) The specification also fails to provide that the recited biomarkers exist in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of these biomarkers exist in such patients with RRMS. Further, it is not well known in the art that these samples provide for the recited biomarkers and that a correlation exists between such biomarkers in the samples with RRMS. The examples in the specification appear to be limited to patients that are human and the detection of the recited biomarkers in either blood, serum or plasma samples from the patients having RRMS. Thus, one cannot practice the claimed invention without undue experimentation.
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.
Claims 1-8 and 10-17 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, step (a) is indefinite in reciting “determining a first level of expression of two or more biomarkers” because the term “determining” appears to intend a mental step; hence, it is unclear if applicant actually intends a positive active method step in the claim. It is suggested but not required to delete the term “determining” and replace it with --detecting--.
Claim 1, step (a) is indefinite in reciting improper Markush language in reciting, “two or more biomarkers selected from” because it appears to intend to limit the scope of the biomarkers but improperly defines it as such. Perhaps, Applicant intends “two or more biomarkers are selected from the group consisting of”.
Claim 4, line 1is indefinite in reciting improper Markush language in reciting, “the therapeutic agent is selected from” because it appears to intend to limit the scope of the therapeutic agent but improperly defines it as such. Perhaps, Applicant intends “the therapeutic agent is selected from the group consisting of”.
Claim 4 the recitation “the therapeutic agent” there is insufficient antecedent basis for this limitation. Although claim 1 recites administering a therapeutically effective amount of a treatment”. The claim does not make clear that the treatment is a therapeutic agent. The current claim could read on a therapeutic amount of rest which is not considered to be a therapeutic agent. Please clarify.
Claim 10, step (a) is indefinite in reciting “determining in a first biological sample from the subject a first level of expression of one or more biomarkers” because the term “determining” appears to intend a mental step; hence, it is unclear if applicant actually intends a positive active method step in the claim. It is suggested but not required to delete the term “determining” and replace it with --detecting--.
Claim 10, step (b) the recitation “the two or more biomarkers and of NfL” is confusing because step (a) only requires one or more markers. Thus, this causes confusion as to whether the Applicant intends that two are more markers must be determined or only one. Please clarify.
Claim 12, is indefinite in reciting “determining the level of expression of” because the term “determining” appears to intend a mental step; hence, it is unclear if applicant actually intends a positive active method step in the claim. It is suggested but not required to delete the term “determining” and replace it with --detecting--.
Claim 13, line 1is indefinite in reciting improper Markush language in reciting, “the therapeutic agent is selected from” because it appears to intend to limit the scope of the therapeutic agent but improperly defines it as such. Perhaps, Applicant intends “the therapeutic agent is selected from the group consisting of”.
Claim 13 the recitation “the therapeutic agent” there is insufficient antecedent basis for this limitation. Although claim 1 recites administering a therapeutically effective amount of a treatment”. The claim does not make clear that the treatment is a therapeutic agent. The current claim could read on a therapeutic amount of rest which is not considered to be a therapeutic agent. Please clarify.
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 1-8 and 10-17 are rejected under 35 U.S.C. 101 because the claimed invention is directed to abstract ideas and/or to laws of nature/natural phenomena without significantly more.
The U.S. Patent and Trademark Office recently revised the MPEP with regard to § 101 (see the MPEP at 2106). Regarding the MPEP at 2106, in determining what concept the claim is “directed to,” we first look to whether the claim recites:
(1) any judicial exceptions, including certain groupings of abstract ideas (i.e., mathematical concepts, certain methods of organizing human activity such as a fundamental economic practice, or mental processes); and
(2) additional elements that integrate the judicial exception into a practical application (see MPEP § 2106.05(a)-(c), (e)-(h)).
Only if a claim (1) recites a judicial exception and (2) does not integrate that exception into a practical application, do we then look to whether the claim contains an “‘inventive concept’ sufficient to ‘transform’” the claimed judicial exception into a patent-eligible application of the judicial exception. Alice, 573 U.S. at 221 (quoting Mayo, 566 U.S. at 82). In so doing, we thus consider whether the claim:
(3) adds a specific limitation beyond the judicial exception that is not “well-understood, routine, conventional” in the field (see MPEP § 2106.05(d)); or
(4) simply appends well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception.
See MPEP 2106.
ELIGIBILITY STEP 2A: WHETHER A CLAIM IS DIRECTED TO A JUDICIAL EXCEPTION
Step 2A, Prong 1
The claims directed to a naturally occurring correlation between the levels of expression of the recited biomarkers in a subject with RRMS compared to a subject or population of subjects in remission from RRMS.
Step 2A, Prong 2
The additional elements of detecting recited biomarker and making a comparison to a population of subjects does not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception.
Also, with respect to the recitation “diagnosing the subject as undergo9ing relapse…”. The “dignosing” statement at best articulates the judicial exception, amounting only to a general instruction to apply or use the judicial exception. This could read on mental activity being performed solely in a practitioner’ head, e.g. A mental appreciation of the recited biomarkers being correlated with a population of subjects. No active method steps are invoked or clearly required; the “diagnosing” statements do not include any activity that would constitute a practical application, i.e. steps that apply, rely on or use the natural principle in a manner such that the claims amount to significantly more that the natural principal itself.
ELIGIBILITY STEP 2B: WHETHER THE ADDITIONAL ELEMENTS CONTRIBUTE AN "INVENTIVE CONCEPT"
Further, the additional elements of the claims are recited with a high level of generality and do not apply, rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. (the active method steps/limitations recited in addition to the judicial exceptions themselves) and do not add significantly more to the judicial exception(s).
As shown by both Hashemipour et al (Iran J Pathol. 2016; 11(4); 334-344) it is well known, routine and conventional to detect two of the recited biomarkers and compare the expression to that of control (e.g. abstract, and throughout the article).
With respect to
With respect to comparing the first level to a second level. Comparison is an abstract idea which can be performed mentally and therefore does not apply, rely on or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. As amended the claims recite “comparing the first level of expression of the two or more biomarkers to a second level of expression of the two..”. As such, the claims recite a step of “comparing” to second level from a population of subjects, such a comparison step is categorized as an abstract idea. As drafted, the comparing step is a process that under its broadest reasonably interpretation, covers performance of the limitation in the mind but for the recitation of a generic analyzer.
With respect to the “administering a therapeutically effective amount of a treatment for RRMA in the subject if the subject is diagnosed as undergoing relapse in (c)” as recited in claims 1 and 10. Although the claim invokes administering a therapeutic as currently recited. The recitation of “if” allows for the scenario when the level is higher indicating the subject is not undergoing relapse and thus allows for an embodiment wherein no therapeutic is administered. Therefore, this scenario does not recite something significantly more than the judicial exception.
It does not appear to be the case that the active steps recited, which are performed in order to gather the data or perform the assay, are steps recited or performed in an unconventional or non-routine way, such to provide an inventive concept under step 2B.
The claimed limitations as currently presented fail to recite limitations that add a feature that is more than well understood, conventional or routine in the field of diagnostics and biochemical assay methodologies.
For all of these reasons, the claims fail to include additional elements that are sufficient to either integrate the judicial exception(s) into practical application(s) thereof, or amount to significantly more than the judicial exception(s).
Allowable Subject Matter
Claims 1-8 and 10-17 would be allowable if rewritten or amended to overcome the rejection(s) under 35 U.S.C. 101, 35 U.S.C. 112(a), and 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action. The prior art of record does not teach nor fairly suggest detecting two or more biomarkers selected from the group consisting of uPA, hK8, hK11 or DSG3 in a sample from a human and comparing the sample to a sample from a subject or a population of subjects in remission from RRMS wherein a lower level is correlated with RRMS.
Conclusion
No claims are allowed.
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Jain (US 2019/0298708) discloses a method detecting neurofilament light chain protein in a sample from subjects with RRMS (e.g. abstract, para 0112).
Schubert et al (US 2016/0054320) discloses methods of treating a patient with MS and relapsing-remitting multiple sclerosis (e.g. para’s 0007-0008, 0023, 0053, 0114).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GARY W COUNTS whose telephone number is (571)272-0817. The examiner can normally be reached M-F 7:00-4:00.
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/GARY COUNTS/ Primary Examiner, Art Unit 1678
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