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 supplemental amendment filed 07/08/23 is acknowledged and has been entered. Claim 23 has been amended. Claims 24-25 and 27 have been canceled. Claims 1-18 and 29-40 were previously canceled. Claims 19-22 and 41-44 remain withdrawn as being directed to non-elected inventions. Accordingly, claims 23, 26 and 28 are under examination.
Withdrawn Rejections
All rejections of claims not reiterated herein, have been withdrawn.
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 23, 26 and 28 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 exosomal ApoA-1 in a subject with NAFLD.
Step 2A, Prong 2
The additional elements of measuring the level of exosomal ApoA-1 protein by contacting the sample with an antibody or aptamer binding specifically to the protein 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 recitations “comparing ApoA-1 protein level measurements between the subject and a normal control” (as recited in claim 23) and “determining the onset of nonalcholic fatty liver disease in the subject when the measurement in the biological sample is lower than that in a sample from a normal control” (as recited in claim 23). The “comparing” and “determining” statements 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 levels in the patient being correlated with that of a normal control and NAFLD. No active method steps are invoked or clearly required; the “comparing” and “determining” 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. Also, with respect to the comparison to the control. 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.
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 Carr et al., (Pediatric Research 89:776-784, available online 26 May 2020) measure exosome ApoA-1 with the use of anti-ApoA-1 antibodies (e.g. page 779). Li et al (Cancer Epidemiol Biomarkers Prev; 2019, pages OF1-OF14) also shows that it is well known, routine and conventional to measure serum eoxsomal ApoA1 with the use of ELISA and antibodies (e.g. abstract, pgs OF3, OF6).
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).
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 23, 26 and 28 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 a method for providing information for measuring a level of exosome-derived (exosomal) ApoA-1 protein in any and all biological samples isolated from a human subject that has nonalcoholic fatty liver disease. 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’, and amount of the biomarker 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 page 17, paragraph 0100, discloses immunoblots of exosmal ApoA-1 obtained from sera of NASH mice. Paragraphs 0102-0103, discloses human serum exosomal ApoA-1 levels in control or NAFLD subjects (human). The specification on pages 29-30, paragraphs 0161-0162, discloses ApoA1 in human serum of healthy subjects and NAFLD subjects and the use of human ELISA for the detection. Paragraph 0162 also discloses the collection of blood, serum and plasma samples. The specification on pages 33-34, paragraph 00182, discloses ApoA-1 protein derived from exosomes decreased in NASH mice and that serum-derived exosomal ApoA-1 decreased in obese patients (humans) with NAFLD compared to the control group. The specification does not provide data, testing or examples with a showing that any all and all biological samples from human subjects provide the recited biomarker at levels which can be specifically correlated with NAFLD.
The only examples utilized in the specification appears to be limited to patients that are mouse or human and the measurement of exosomal ApoA-1 in either blood, serum or plasma samples from the human or mouse for diagnosing NAFLD. 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 NAFLD. As stated supra the specification appears to be limited to patients that are mouse or human and the measurement of exosomal ApoA-1 in either blood, serum or plasma samples from the mouse or human for analyzing NAFLD.
The specification also fails to provide that the recited exosomal ApoA-1 exists in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue and that a correlation of this biomarker exist in such patients with NAFLD. Further, it is not well known in the art that these samples provide for the recited biomarker and that a correlation exists between such biomarker in the samples to assess NAFLD. The examples in the specification appear to be limited to patients that are mouse or human and the measurement of decreased levels in either blood, serum or plasma samples from the patients for diagnosing NAFLD. 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 measurement of the recited biomarker in any and all biological samples from any and all subjects wherein any amount, presence or absence of the biomarkers is directly correlated with NAFLD.
Response to Arguments
Applicant's arguments filed 07/08/26 have been fully considered but they are not persuasive.
101 Rejections:
Applicant argues that claim 23 recites physical action steps and is directed to a method requiring a defined laboratory procedure, including: physically contacting a biological sample with an antibody or aptamer, measuring a protein level using that binding interaction, comparing measured values to a control, and determining the onset of NAFLD and that these steps require human intervention and manipulation of a physical biological sample using specific detection techniques. Applicant states that the claim 23 does not recite “a correlation”, but instead, recites a specific, multi-step detection procedure grounded in phys8ical action steps.
This argument and statement are not found persuasive because (1) the steps of measuring the ApoA-1 protein by contacting the biological sample with an antibody or aptamer that specifically binds to the protein are considered to be additional elements that do not rely on, or use the judicial exception in a manner that imposes a meaningful limit on the judicial exception. Thus, the additional elements which are well known, routine and conventional are considered to be insignificant extra-solution activity and are insignificant steps of data gathering. (2) the “comparing” and “determining” statements 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 levels in the patient being correlated with that of a normal control and NAFLD. No active method steps are invoked or clearly required; the “comparing” and “determining” 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. Also, with respect to the comparison to the control. 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. (3) the claim specifically recites “determining that the onset of nonalcoholic fatty liver disease in the subject when the measurement in the biological sample is lower than that in a sample from a normal control” and therefore is reciting a correlation of the level in the subject with that of NAFLD. (4) the recognition in the biomarker as being decreased in the subjects is the judicial exception.
112 (a) Written Description:
Applicant argues that the Office’s concern regarding unsupported “biological samples” is misplaced. Applicant argues that the claims are directed to detection of exosome-derived ApoA-1 protein and that the specification describes exemplary biological samples including tissues, cells, whole blood, sera and plasma isolated from a subject and that the specification consistently exemplifies measurement in blood-derived samples including serum and plasma. Applicant states that these exemplary embodiments and samples represent clinically relevant biological samples for detecting exosomal biomarkers.
This argument and statement are not found persuasive because the instant claims are not merely directed to the detection of exosome-derived ApoA-l protein in a biological sample but are more importantly directed to the measurement of the ApoA-1 and the very specific correlation of a decrease amount in the sample being correlated specifically with NAFLD. As stated supra and in the previous office action the Applicant has not provided evidence that the ApoA-1 protein which appears in decreased levels in NAFLD humans also appears in a biological sample such as sputum, tears, peritoneal fluid etc and to also appear as decreased levels in NAFLD. The applicant has not provided any reasoning, evidence or data that what appears at a specific level in blood, serum or plasma is also expected to appear in the same fashion in sputum, liquid stool, peritoneal fluid, tears etc. A showing of blood, serum of plasma and a specific correlation of decreased levels in NAFLD is not a showing that any and all biological samples would possess the ApoA-1 biomarker and that one of skill would also expect the ApoA-1 to be decreased in all possible biological samples and at levels which are specifically correlated with NAFLD.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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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