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 Claims
Claims 1-8 and 14 are pending and examined herein.
Specification
The disclosure is objected to because it contains an embedded hyperlink on pg. 12, line 256 https://www.uniprot.org. 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.
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.
Claim 2, 5-6, and 8 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
Claim 2 recites the biological sample is at least one selected from the group consisting of blood, whole blood, serum, urine, saliva, tissue, cell, organ, bone marrow, fine needle aspirate, core needle biopsy sample, and vacuum aspiration biopsy sample.
The specification discloses experimental results obtained using only two types of samples: aortic cells (Experimental Example 2, pg. 25) and blood (Experimental Example 7, pg. 28).
The prior art is silent on using the biomarkers of claim 1 for diagnosing aortic stenosis or determining that the prognosis of aortic stenosis.
The art of biomarkers for diagnosing diseases is highly unpredictable; therefore, Applicant needs to provide evidence that the biomarkers of claim 1 can be used in the claimed method with the biological samples other than blood and aortic cells.
Claims 5-6 recite the prognosis is at least one selected from the group consisting of occurrence, severity, recurrence, disease free survival, degeneration of the aortic valve, and the occurrence of complications related to aortic stenosis; and the complication is at least one selected from the group consisting of hypertension, rheumatoid arthritis, and interstitial lung disease.
The specification discloses patient characteristics by titer group of anti-citrullinated peptide antibodies (Example 3-1 and Table 2, pg. 33), wherein hypertension, rheumatoid arthritis, and interstitial lung disease are listed as patient’s other disease conditions. However, the specification fails to disclose data for hypertension, rheumatoid arthritis, and interstitial lung disease being complications caused by aortic stenosis. There are no data linking hypertension, rheumatoid arthritis, and interstitial lung disease to the diagnosed condition of aortic stenosis. The prior art is silent on this matter.
Example 3-2 (pg. 35-36) and Table 3 (pg. 36) disclose results of a follow-up study of the patients, but they fail to disclose data related to prognostic value of the biomarkers for severity, recurrence, disease free survival, degeneration of the aortic valve, and the occurrence of complications related to aortic stenosis. Table 3 discloses data for AS progression only (row 2).
Claim 8 recites the aortic stenosis is accompanied by calcification of the aortic valve. The specification discloses that for patients participating in the study aortic valve degeneration was defined when the leaflet of the aortic valve thickened or when at least one of the leaflets underwent calcification (Experimental Example 6, pg. 28, lines 606-607). Aortic valve degeneration defined by thickened leaflet means that non all patients had calcification. The specification fails to provide evidence for calcification of the aortic valve and its diagnosing using citrullinated biomarkers of claim 1. The prior art is silent on this matter.
Based on the above findings, one of ordinary skill in the art would conclude that Applicant did not have possession of the claimed invention at the time the application was originally filed.
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 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 recites “a control group” (last line of step S3). Step S2 already recites a control group (last line). It is unclear if step S3 recites the same control group as in step S2 or a different control group. Claims 2-8 are rejected because they depend from rejected claim 1.
Claim 2 recites blood and whole blood. The difference between blood and whole blood is unclear.
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 14 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring correlation, without significantly more.
Claims 1 and 14 are directed to a process, which belongs to the four statutory categories.
The claims are related to methods of establishing a relationship between diagnosis of aortic stenosis or determining that the prognosis of aortic stenosis is unfavorable and a measurement of: (a) at least one selected from the group consisting of a level of anti-citrullinated peptide antibodies, a level of citrullinated protein, and an activity degree of citrullinated protein from a biological sample separated from a test subject (claim 1); or (b) a level of anti-citrullinated peptide antibodies (claim 14). This relationship is categorized as a naturally occurring correlation, and therefore it is a judicial exception.
The claims also recite an additional step of measuring (S1) and confirming (S2). The additional step of “measuring” is an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
The additional step of “confirming” amounts to a mental process, namely concepts performed in the human mind, since confirming is considered an observation, evaluation, and/or a judgement. The limitation of “confirming” falls into the mental process groupings of abstract ideas and therefore is a judicial exception.
The additional step of “diagnosing” amounts to making a conclusion based on the results of steps S1 and S2 that the human patient suffers from aortic stenosis or determining that the prognosis of aortic stenosis is unfavorable. The step of “diagnosing” amounts to a mental process, performed in the human mind, since diagnosing is considered an observation, evaluation, and/or a judgement. The limitation of “diagnosing” falls into the mental process groupings of abstract ideas and therefore is a judicial exception.
The claims recite an additional step of treating the aortic stenosis with chemotherapy. Although this limitation indicates that a treatment is to be administered, it does not provide any information as to how the patient is to be treated, or what the treatment is, but instead covers any possible treatment that a doctor decides to administer to the patient - “treating the aortic stenosis with chemotherapy.” This limitation is recited at a high level of generality, it tells the doctors about the naturally occurring correlation, and at most adds a suggestion that the doctors take this correlation into account when treating their patients. The limitation of treating thus fails to meaningfully limit the claim because it does not require any particular medication or treatment, and is at best the equivalent of merely adding the words “apply it” to the judicial exception. Accordingly, the limitation of treating does not integrate the recited judicial exception into a practical application and the claims are therefore directed to the judicial exception.
When considering the elements in combination, the claims as a whole do not integrate the recited exceptions into a practical application.
Additional elements of measuring recited biomarkers are recited at a high level of generality: a measurement of a level of anti-citrullinated peptide antibodies, a level of citrullinated protein, or an activity degree of citrullinated protein. These measurements have been recognized as routine laboratory techniques.
The techniques for measuring a level of citrullinated protein are known in the art. It was routine and conventional to measure citrullinated histone H3 expression by immunostaining (Abstract), see Kopytek et al. (IDS; Int J Cardiol. 2019 Jul 1; 286:121-126).
Therefore, the claims as a whole do not amount to significantly more than the recited exception, because there are no additional elements, or combination of additional elements, that add an inventive concept to the claims and are not routine and conventional.
The dependent claims 2-8 fail to add additional elements, or combination of additional elements, that contribute to an inventive concept to the claim.
For these reasons, claims 1-8 and 14 are ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determining the scope and contents of the prior art.
Ascertaining the differences between the prior art and the claims at issue.
Resolving the level of ordinary skill in the pertinent art.
Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over Kopytek et al. (IDS; Int J Cardiol. 2019 Jul 1; 286:121-126) in view of Marquis-Gravel et al. (Circulation. 2016 Nov 29;134(22):1766-1784).
Regarding claim 1, Kopytek teaches a method comprising:
measuring a level of citrullinated protein from a biological sample separated from a test subject – specifically, valvular expression and plasma levels of citrullinated histone H3 (citH3) were determined (Abstract. Methods);
confirming whether the level of citrullinated protein is increased compared to a control group – specifically, amount of valvular citH3-positive cells was higher in aortic stenosis (AS) patients compared with controls and correlated with aortic valve area (Abstract. Results);
diagnosing as aortic stenosis – specifically, the reference teaches that “In AS patients the amount of valvular citH3 correlated with the disease severity measured as AVA (Fig. 3B)” and “AS patients plasma citH3 levels were also associated with AVA (Fig. 3D)” (pg. 122, col. 2, section “3.4. citH3 associations”), where AVA is aortic valve area. Kopytek does not explicitly teach the step of diagnosing aortic stenosis, but since, the amount of valvular citH3-positive cells was higher in aortic stenosis, one of ordinary skill in the art would have found it obvious to diagnose patients with higher amounts of citH3-positive cells as having arterial stenosis.
Kopytek does not specifically teach treating the aortic stenosis with chemotherapy.
Regarding claim 1, Marquis-Gravel teaches medical treatment of patients with aortic
stenosis (Abstract). Marquis-Gravel teaches ACE inhibitors as one of the therapies for treating aortic stenosis (pg. 1770, col. 2, last par.). ACE inhibitors are one of the medications defined by Applicant as “chemotherapy” (pg. 23, lines 507-510).
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kopytek by employing treatment with ACE inhibitors as taught by Marquis-Gravel, in order to provide medical care for patients diagnosed with aortic stenosis. One having ordinary skill in the art would have been motivated to treat patients diagnosed with aortic stenosis because it is a routine practice in healthcare to treat a diagnosed serious medical condition. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Marquis-Gravel teaches treatment with ACE inhibitors of patients diagnosed with aortic stenosis.
Regarding claim 2, Kopytek teaches valvular expression and plasma levels of citrullinated histone H3 (citH3) (Abstract. Methods) meeting the limitations of claim 2 reciting organ.
Regarding claim 3, Kopytek teaches that aortic valves were obtained at autopsy from age-matched apparently healthy subjects, without morphological valvular or other cardiac disorders served as negative control (pg. 122, col. 1, section “Patients”) meeting the limitation reciting the control group is a biological sample separated from a normal individual.
Regarding claims 4-5, Kopytek teaches that aortic valves were obtained at autopsy from age-matched apparently healthy subjects, without morphological valvular or other cardiac disorders served as negative control (pg. 122, col. 1, section “Patients”) meeting the limitation reciting the control group is a biological sample separated from a normal individual.
The reference teaches that amount of valvular citH3-positive cells was higher in aortic stenosis (AS) patients compared with controls and correlated with aortic valve area (Abstract. Results). The aortic valve area (AVA) is a measure of the severity of aortic stenosis. Therefore, Kopytek teaches the prognosis of severity.
Claim 7 is rejected under 35 U.S.C. 103 as being unpatentable over Kopytek and Marquis-Gravel, further in view of Midwood et al. (PGPub 20160327556) and as evidenced by Sakkas et al. (Autoimmun Rev. 2014 Nov;13(11):1114-20).
The teachings of Kopytek and Marquis-Gravel have been set forth above.
Kopytek and Marquis-Gravel do not specifically teach a method of measurement of the level of the anti-citrullinated peptide antibodies.
Regarding claim 7, Midwood teaches determining the inflammatory disorder status of a subject by detecting autoantibodies with specificity for citrullinated tenascin-C and/or fragments of citrullinated tenascin-C (Abstract). The reference teaches that the inflammatory disorder may be associated with any condition associated with inappropriate inflammation, including cardiovascular disease ([0025]). Aortic stenosis is a cardiovascular disease. Specifically, Midwood teaches that western blotting can be used for detection of autoantibodies having specificity for citrullinated tenascin-C and/or fragments of citrullinated tenascin-C ([0036]).
Sakkas provides evidence that anti-citrullinated peptide autoantibodies are directed against different citrullinated antigens, including fibrinogen, fibronectin, α-enolase, collagen type II, histones. Kopytek teaches citrullination of histone H3.
It would have been obvious to one having ordinary skill in the art before the effective filing date of the claimed invention to modify the method of Kopytek and Marquis-Gravel by employing detection of autoantibodies with specificity for citrullinated peptide as taught by Midwood, in order to use autoantibodies as an additional biomarker for citrullinated peptides in patients with aortic stenosis. One having ordinary skill in the art would have been motivated to add another biomarker for detecting citrullinated peptides because the additional biomarker can improve reliability of the detection. This combination would have been desirable to those of ordinary skill in the art for the reasons mentioned above.
One having ordinary skill in the art would have had a reasonable expectation of success in combining the prior art references because Midwood teaches detecting autoantibodies with specificity for a citrullinated peptide.
Subject Matter Free of the Prior Art
Claims 6, 8, and 14 are free of the prior art.
The prior art neither teaches nor suggests a method for diagnosing aortic stenosis or determining an unfavorable prognosis of aortic stenosis and treating the condition, wherein the prognosis includes the occurrence of complications related to aortic stenosis, wherein the complication is at least one selected from the group consisting of hypertension, rheumatoid arthritis, and interstitial lung disease; the aortic stenosis is accompanied by calcification of the aortic valve; and the anti-citrullinated peptide antibodies levels are >10 U/mL for FEIA or >5.0 U/mL for CMIA.
The closest prior art:
Kopytek teaches increased level of citrullinated protein in aortic stenosis patients, but fails to teach any complications of this condition, calcification of the aortic valve, or specific levels of anti-citrullinated peptide antibodies;
Marquis-Gravel teaches medical treatments for patients with aortic stenosis, but fails to teach any complications of this condition, calcification of the aortic valve, or specific levels of anti-citrullinated peptide antibodies;
Midwood teaches detecting autoantibodies with specificity for citrullinated tenascin-C, but fails to teach any complications of this condition, calcification of the aortic valve, or specific levels of anti-citrullinated peptide antibodies.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Alexander Volkov whose telephone number is (571) 272-1899. The examiner can normally be reached M-F 9:00AM-5:00PM (EST).
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Bao-Thuy Nguyen can be reached on (571) 272-0824. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/ALEXANDER ALEXANDROVIC VOLKOV/
Examiner, Art Unit 1677
/REBECCA M GIERE/Primary Examiner, Art Unit 1677
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