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 .
Claims 1-18, 22, and 26 are pending and currently under consideration.
Information Disclosure Statement
Cite No. 1 of the information disclosure statement filed 10/31/23 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because the “Number” describing the U.S. patent or application appears to be incorrect. The number listed with Cite No. 1 is 2016/061824. The number 2016/061824 is not a U.S. patent or application. It appears Applicant may have intended to provide the number 2016/0061824 of Hahn et al (US 2016/0061824 A1; 3/3/2016). Hahn et al is cited in the attached PTO-892. Applicant is advised that the date of any re-submission of any item of information contained in this information disclosure statement or the submission of any missing element(s) will be the date of submission for purposes of determining compliance with the requirements based on the time of filing the statement, including all certification requirements for statements under 37 CFR 1.97(e). See MPEP § 609.05(a).
Claim Rejections - 35 USC § 112
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 5-6 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.
Claims 5-6 are rejected because claim 5 recites “…isoform, such as histone isoform of a core nucleosome, in particular histone H3 isoform.” The metes-and-bounds of the claims are unclear because it is unclear how, or if, text following “such as” and “in particular” limit the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1, 2, 4, 5, 7-10, 13, 15, 17, 18, and 22 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Hahn et al (US 2016/0061824 A1; 3/3/2016).
Hahn et al cites references teaching neutrophil extracellular traps (NETs) have been implicated in the etiology of inflammatory conditions such as multiple sclerosis ([0005}, in particular) and that NETs can be generated by a distinct processes of cell death (NETosis) and that the molecular pathway leading to NETosis involve citrullination of histone H3 ([0004], in particular). Hahn et al further teaches a method for detecting/diagnosing an inflammatory disorder in a subject comprising detecting cell-free nucleosomes in a serum or plasma sample isolated from said subject ([0015], in particular). Hahn et al further teaches said method wherein the inflammatory disorder is multiple sclerosis ([0038], in particular). Hahn et al further teaches said method wherein the cell-free nucleosomes are detected by contacting the serum or plasma sample with one or more reagents which specifically binds cell-free nucleosomes and/or one or more reagents which specifically binds modified DNA of cell-free nucleosome and/or one or more reagents which bind a modified protein of a cell-free nucleosomes wherein specific binding of the one or more agents to the modified histone protein and/or modified DNA of the cell-free nucleosome is indicative of the presence of said inflammatory disorder ([0022]-[0023]; note: detecting modified protein of a cell-free nucleosome and detecting modified DNA of a cell-free nucleosome is detecting a “panel”, in particular). Detecting multiple sclerosis by the method of Hahn et al detects a subject in need of medical treatment for multiple sclerosis, as recited by instant claim 22. Hahn et al further teaches said method wherein the modified histone protein is methylation or histone H3 deimination ([0034] and note that methylation and deimination are “post-translational modifications” that are epigenetic features, in particular). ). Hahn et al further teaches said method wherein the level of cell free nucleosomes is measured using an immunoassay wherein the one or more reagents which specifically binds a modified protein is an antibody ([0027], in particular). Hahn et al further teaches immobilizing cell-free nucleosomes or modified histones of cell-free nucleosomes on a solid suspended in liquid and that reagents of Hahn et al can be detectably labeled ([0026], in particular). Hahn et al further teaches said method wherein the subject is human ([0039], in particular). Hahn et al further teaches said method wherein the method is performed pre-treatment and is repeated post-treatment and a decrease in the level of cell-free nucleosomes, as compared to pre-treatment (“control”) is indicative of efficacy of the treatment ([0101], in particular).
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.
Claim(s) 1, 2, 4-10, 13, 15, 17, 18, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hahn et al (US 2016/0061824 A1; 3/3/2016) as applied to claims 1, 2, 4, 5, 7-10, 13, 15, 17, 18, and 22 above, and further in view of Scott et al (Frontiers in Cell and Developmental Biology, 2020, 8(Article 701): 1-21).
Teachings of Hahn et al are discussed above.
Hahn et al does not specifically teach a method where the modified histone protein H3 of the cell-free nucleosome indicative of the presence of multiple sclerosis is a modified H3.1 histone protein. Hahn does not specify which isoform of H3 is detected. However, these deficiencies are made up in the teachings of Scott et al.
Scott et al is a review article that cites numerous references teaching isoforms of histone H3 known in the prior art include: H3.1, H3.2, H3.3, H3t/H3.4, H3.5, H3.Y, H3.X, CENP-A, H3.3-like H3.6, H3.8, H3.1-like H3.7 (left column on page 2, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method of Hahn et al wherein the modified histone protein H3 histone protein is a modified H3 histone protein that is any histone H3 isoform, such as H3.1, because Hahn et al does not teach any preference of H3 isoform for the detection of the modified histone protein H3. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1-5, 7-10, 13, 15, 17, 18, and 22 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hahn et al (US 2016/0061824 A1; 3/3/2016) as applied to claims 1, 2, 4, 5, 7-10, 13, 15, 17, 18, and 22 above, and further in view of Holdenrieder et al (Critical Reviews in Clinical Laboratory Sciences, 2009, 46(1): 1-24; 10/31/23 IDS).
Teachings of Hahn et al are discussed above.
Hahn et al does not specifically teach a method where the sample in which modified histone protein H3 of the cell-free nucleosome indicative of the presence of multiple sclerosis is measured is cerebrospinal fluid. However, these deficiencies are made up in the teachings of Holdenrieder et al.
Holdenrieder et al teaches cerebrospinal fluid as a source of circulating nucleosomes (column spanning page 18, in particular).
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform the method of Hahn et al wherein the modified histone protein H3 histone protein is detected in just any sample that has been demonstrated to be a source of circulating nucleosomes, including cerebrospinal fluid of Holdenrieder et al, because Holdenrieder et al teaches cerebrospinal fluid as a source of circulating nucleosomes and the method of Hahn et al detects multiple sclerosis by detecting modified histone protein H3 of the cell-free (same as “circulating”) nucleosomes. This is an example of some teaching in the prior art that would have led one of ordinary skill to modify the prior art reference to arrive at the claimed invention. Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
Claim Rejections - 35 USC § 103
Claim(s) 1, 2, 4, 5, 7-18, 22, and 26 is/are rejected under 35 U.S.C. 103 as being unpatentable over Hahn et al (US 2016/0061824 A1; 3/3/2016) as applied to claims 1, 2, 4, 5, 7-10, 13, 15, 17, 18, and 22 above, and further in view of Naegele et al (Journal of Neuroimmunology, 2012, 242: 60-71) and Rahier et al (Clinical Epigenetics, 2017, 9(53): 1-7).
Teachings of Hahn et al are discussed above.
Hahn et al does not specifically teach the recited method wherein a comparison is made to a healthy subject, the recited method wherein the subject is administered a treatment, or detecting cell-free nucleosomes indicative of multiple sclerosis by (i) contacting the serum or plasma sample with a first binding agent that binds citrullinated histone H3 (or a first binding agent that binds a cell free nucleosome), (ii) contacting the sample bound with the fist binding agent with a second binding agent that binds a cell free nucleosome (or a second binding agent that binds citrullinated histone H3), and (iii) detecting or quantitating the binding of the second binding agent in the sample. However, these deficiencies are made up in the teachings of Naegele et al and Rahier et al.
Naegele et al teaches neutrophils in multiple sclerosis patients exhibit higher neutrophil extracellular traps (NETs) in serum (Figure 1, in particular) and that nucleosomes derived NETosis are elevated in multiple sclerosis patients as compared to healthy controls (left column on page 68 and paragraph spanning pages 63-64, in particular). As taught by Hahn et al (at [0004]), such NETosis involves citrullination of histone H3.
Rahier et al teaches a method of measuring levels of cell-free nucleosomes in serum exhibiting nucleosome markers of a disorder comprising (i) contacting the serum with a first binding agent that binds cell free nucleosomes, (ii) contacting the sample bound with the first binding agent with a second binding agent that binds a nucleosome marker of a disorder, and (iii) detecting or quantitating the binding of the second binding agent in the sample (see Circulating cf-nucleosome ELISA beginning on the right column on page 2, in particular)
One of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform a combined method for detecting and treating multiple sclerosis in a subject comprising using a modified Circulating cf-nucleosome ELISA capture method of Rahier et al to detect a modified protein of a cell-free nucleosomes of Hahn et al, such as methylated or citrullinated histone H3, in serum from the subject wherein the methylated or citrullinated histone H3 of cell-free nucleosomes is detected and the subject is treated by (i) contacting the serum with a first binding agent that binds cell free nucleosomes to “capture” cell free nucleosomes (or an alternate method where the first binding agent binds methylated or citrullinated histone H3), (ii) contacting the sample bound/captured with the first binding agent with a second binding agent that binds methylated or citrullinated histone H3 (or in said alternate method where the second binding agent binds cell free nucleosomes), (iii) detecting or quantitating the binding of the second binding agent in the sample, and (iv) comparing the level of binding of the second binding agent in the sample to binding in controls from a healthy subject and wherein subjects with elevated levels are indicated as having multiple sclerosis and administered a therapeutic treatment for multiple sclerosis because elevated levels of methylated or citrullinated (due to NETosis) histone H3 of cell-free nucleosomes is indicative of multiple sclerosis (as taught by Hahn et al) and the Circulating cf-nucleosome ELISA capture method of Rahier et al effectively detects markers of disorders found on cell free nucleosomes based on the ability to bind both a binding agent for cell free nucleosomes and a binding agent for the marker of the disorder found on nucleosomes. Substituting binding agents for methylated or citrullinated histone H3 in place of the binding agent for the marker of the disorder of Rahier et al is an example of a simple substitution of one known element for another to obtain predictable results. Further, one of skill in the art would recognize that using the binding agent for a marker for a disorder as the first “capture” binding agent and the binding agent for cell free nucleosomes as the second binding agent in the modified Circulating cf-nucleosome ELISA capture method of Rahier et al would predictably result in detecting levels of markers of disorders found on nucleosomes because the second binding agent would detect captured level of the marker for a disorder that are found on nucleosomes. This is also an example of applying a known technique (a Circulating cf-nucleosome ELISA capture method) to a method of Hahn et al ready for improvement (to specifically detect methylated or citrullinated histone H3 of cell-free nucleosomes) to yield predictable results. See MPEP 2143.
Further, of ordinary skill in the art would have been motivated, with a reasonable expectation of success, to perform said combined method with said subject after treatment of the subject for multiple sclerosis in order to determine presence of multiple sclerosis after treatment and/or the response of the subject to the treatment because Hahn et al teaches the modified histone protein of cell free nucleosomes is indicative of the presence of an inflammatory disorder such as multiple sclerosis ([0024] and [0038], in particular) and decrease in the level of cell-free nucleosomes, as compared to pre-treatment (“control”) is indicative of efficacy of the treatment ([0101], in particular).
Therefore, the invention as a whole would have been prima facie obvious to one of ordinary skill in the art, absent unexpected results.
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 1-18, 22, and 26 are rejected under 35 U.S.C. 101 because the claimed invention is directed to judicial exception(s) (i.e., a law of nature, a natural phenomenon, and/or an abstract idea) without significantly more. The rationale for this determination is explained below:
Claims 1-18, 22, and 26 are directed to natural phenomenon because the claims recite natural phenomenon (“Step 2A prong one”) and the judicial exception(s) is/are not integrated into a practical application (“Step 2A prong two”). The “natural phenomenon” is: levels of cell free nucleosomes, or components thereof, in biological samples are indictive of multiple sclerosis and/or need for medical treatment for multiple sclerosis. It is noted claim 26 recites a treatment step; however, the treatment step is generic and does not require any particular treatment and is equivalent to an “apply it” step (see MPEP 2106.04(d)(2)). Therefore, the treatment step of claim 26 does not integrate the judicial exception(s) into a practical application. MPEP 2106.04(d)(2) indicates a claim reciting a judicial exception is not directed to a judicial exception if it also recites additional elements(s) demonstrating the claim as a whole integrates the exception into a practical application by using recited judicial exceptions to effect a particular treatment or prophylaxis that has more than a nominal or insignificant relationship to the exception(s) (see aspirin example under “Whether The Limitation(s) Have More Than A Nominal Or Insignificant Relationship To The Exception(s)” at MPEP 2106.04(d)(2)). In the instant situation, there is not more than a “nominal or insignificant relationship” between the recited judicial exception and the step of administering just any treatment. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception(s). A claim that focuses on judicial exception(s) can be shown to recite something “significantly more” than the judicial exception(s) by reciting a meaningful limitation beyond the judicial exceptions. However, in the instant case, the claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (when considered both individually and as an ordered combination) are limited to well-understood, routine and conventional limitations of detecting levels of cell free nucleosomes, or components thereof, in biological samples and optionally treating a subject suffering from multiple sclerosis (“Step 2B”). Well-understood, routine and conventional limitations are not meaningful limitations and are not enough to qualify the claimed method as reciting something “significantly more” than the judicial exception(s) (see Part I.B.1 of the interim Guidance).
MPEP 2106.05(d)(II) provides a non-limiting list of laboratory techniques recognized by courts as well-understood, routine, conventional activity. These techniques include:
i. Determining the level of a biomarker in blood by any means, Mayo, 566 U.S. at 79, 101 USPQ2d at 1968; Cleveland Clinic Foundation v. True Health Diagnostics, LLC, 859 F.3d 1352, 1362, 123 USPQ2d 1081, 1088 (Fed. Cir. 2017);
PNG
media_image1.png
18
19
media_image1.png
Greyscale
Detecting cell free nucleosomes, and components thereof, by contacting body fluid samples with binding agent is routine, conventional, and well known in the art (see [0022]-[0023] of Hahn et al (US 2016/0061824 A1; 3/3/2016) and Circulating cf-nucleosome ELISA beginning on the right column on page 2 of Rahier et al (Clinical Epigenetics, 2017, 9(53): 1-7), for example). Here, the claims do not contain any significant additional elements or steps beyond the observation of judicial exception(s) present when performing routine and conventional methods. Further, the active method steps are conventional and routine in the art for the reasons stated above and the claims do not amount to significantly more than the judicial exception(s). Further, just as methods comprising detecting paternal DNA sequences in particular samples by PCR was identified in Ariosa v. Sequenom as "well-known, routine, and conventional" (see first paragraph on page 13 of Ariosa Diagnostics, Inc. v. Sequenom, Inc. (Fed. Cir. 2015)) even though the prior art did not demonstrate detecting said paternal DNA sequences in said particular samples by PCR, the methods encompassed by the instant claims are well-known, routine, and conventional. The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the additional elements (common methods of detecting expression) are routinely performed in the art to obtain data regarding expression and treat subjects. In regards to “diagnosing", it is further noted that merely presenting results of a process otherwise unpatentable under 35 U.S.C. 101 is insufficient to establish eligibility under the statute. See FairWarning IP, LLC v. Iatric Sys., Inc., No. 2015-1985, 2016 WL 5899185, at *3 (Fed. Cir. Oct. 11, 2016) (claim unpatentable under 35 U.S.C. 101 despite recitation of the step: “providing notification if [an] event has occurred”). Moreover, “[w]hile preemption may signal patent ineligible subject matter, the absence of complete preemption does not demonstrate patent eligibility…." Ariosa Diagnostics, Inc., v. Sequenom, Inc., 788 F.3d 1371, 1379 (Fed. Cir. 2015), cert. denied, No. 15-1182, 2016 WL 1117246 (U.S. June 27, 2016). Further, “Groundbreaking, innovative, or even brilliant discovery does not by itself satisfy the § 101 inquiry.” Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 133 S. Ct. 2107, 2117 (2013). The claims do not recite something “significantly more” than the judicial exception(s); rather, the claims “simply inform” the natural phenomenon to one performing routine active method steps and do not amount to significantly more than the judicial exception(s).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SEAN E AEDER whose telephone number is (571)272-8787. The examiner can normally be reached M-F 9am-6pm ET.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Samira Jean-Louis can be reached at (571)270-3503. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/SEAN E AEDER/ Primary Examiner, Art Unit 1642