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 Group II, claims 23-28 in the reply filed on 02/19/26 is acknowledged. Currently, claims 19-28 and 41-44 are pending. Claims 19-22 and 41-44 are withdrawn as being directed to non-elected inventions. Accordingly, claims 23-28 are under examination.
NOTE: There was a discrepancy in the response filed 02/19/26. Specifically, the Applicant elected Group II claims 23-28 and stated that the claims were drawn to a composition. The Examiner called Kisuk Lee, Attorney on 03/12/26 and informed the Applicant that claims 23-28 were drawn to a method and not a composition. Mr. Lee confirmed that the election was indeed intended to be Group II, claims 23-28 directed to a method.
Abstract
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The instant abstract utilized implied phrases see “The present invention relates to”. This language should be avoided.
Specification
The disclosure is objected to because it contains an embedded hyperlink and/or other form of browser-executable code (e.g. page 22, paragraph 0130 and page 25, line 1). Applicant is required to delete the embedded hyperlink and/or other form of browser-executable code; references to websites should be limited to the top-level domain name without any prefix such as http:// or other browser-executable code. See MPEP § 608.01.
The disclosure is objected to because of the following informalities: On page 29, paragraph 00161, the disclosure “exosomal ApA-1” should be --exosomal ApoA-1--.
Appropriate correction is required.
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 § 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 23-28 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 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 protein level measurments between the subject an a normal control” (as recited in claim 24) 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 27). 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 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 23-28 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 diagnosis of nonalchoholic fatty liver disease (NAFLD) by measuring a level of exosome-derived (exosomal) ApoA-1 protein in any and all biological samples isolated from any and all subjects that has developed or is suspected of onset of nonalcoholic fatty liver disease and allowing for any possible increases, decreases, presence, absence or equal amounts for analyzing NAFLD. The limitation 'subject’ represents a genus and encompasses human and non-human including 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. Also, the current claim broadly allows for the determination of any and all increases, decreases, presence, absence or equal amounts of the biomarker for analyzing NAFLD. 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 any and all subjects provide the recited biomarker at levels which can be specifically correlated with NAFLD. 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 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 for a correlation of the recited biomarkers in all patients such as dogs, cats, cows, monkey, horse, rabbits and squirrel (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 exosomal ApoA-1 exists in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of this biomarkers 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.
Scope of Enablement
Claims 23-28 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for diagnosing nonalcoholic fatty liver disease in a mouse or human subject comprising obtaining a blood, serum or plasma sample from the subject, measuring the level of exosomal ApoA-1 in the sample, comparing the level to that of a control; wherein a deceased amount as compared to that of the control indicates the subject as having NAFLD. 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 a method for providing information for diagnosis of nonalchoholic fatty liver disease (NAFLD) by measuring a level of exosome-derived (exosomal) ApoA-1 protein in any and all biological samples isolated from any and all subjects that has developed or is suspected of onset of nonalcoholic fatty liver disease and allowing for any possible increases, decreases, presence, absence or equal amounts for analyzing NAFLD.
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 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 any and all subjects provide the recited biomarker at levels which can be specifically correlated with NAFLD. 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 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 for a correlation of the recited biomarkers in all patients such as dogs, cats, cows, monkey, horse, rabbits and squirrel (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 exosomal ApoA-1 exists in samples such as lung tissue, kidney tissue, stool, saliva, tears, sputum, CSF or liver tissue or that a correlation of this biomarkers 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 diagnosing nonalcoholic fatty liver disease in a mouse or human subject comprising obtaining a blood, serum or plasma sample from the subject, measuring the level of exosomal ApoA-1 in the sample, comparing the level to that of a control; wherein a deceased amount as compared to that of the control indicates the subject as having NAFLD. 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.
Claim 24 is 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 24 the recitation “protein level measurements” is vague and indefinite because it is unclear if the applicant is referring to the exosome-derived ApoA-1 protein, an additional protein or if the applicant intends something else. Please clarify.
Allowable Subject Matter
Claims 23-28 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 measuring exosomal ApoA-1 protein and correcting with NAFLD as currently recited.
Conclusion
No claims are allowed.
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