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 .
DETAILED ACTION
Priority
This application is a continuation-in-part of International Patent Application No. PCT/US23/74164, filed September 14, 2023, which claims priority to U.S. Application No. 63/406,830 filed on September 15, 2022 that is hereby acknowledged by the Examiner.
Status of the Claims
The amendment dated 12/18/2023 is acknowledged. Claims 1-19 are pending and under examination.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 02/09/2024 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement(s) is/are being considered by the Examiner.
Drawings
The drawing filed on 09/26/2023 are acknowledged and accepted by the Examiner.
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 1-13 are rejected under 35 U.S.C. 101 because the claims are directed to providing a treatment for chronic HBV to the subject based on the presence of HBV particles at a threshold value, which appears to be a correlation with no step as to said treatment (i.e. a treatment step if the markers are low or a treatment step if the markers are high). The claims do not include additional elements that are sufficient to amount to significantly more than the judicial exceptions because the claims recite methods that are making use of a natural principle/correlation. The claim involves steps of comparing the values for the measurements obtained (a mental step/abstract idea). The claim also involves steps of making a correlation between the expression level of genes and a subject' s response to chronic HBV treatment (non-phosphorylated HBcAg versus phosphorylated HBcAg (P-HBcAg) status to likelihood of responding to a therapy). Thus, the comparing steps are at a high level of generality, and are necessary data gathering steps required in order to apply the natural correlation.
Additionally, claim 1 recites steps for making measurements, wherein the “measuring" is an additional step in addition to the judicial exception. The method steps do not impose meaningful limits on the claim scope, which is the correlation of the phosphorylated status of HBcAgs. The only element “in addition” to the JE is the step of measuring the levels (e.g. HBcAg and P-HBcAg in a sample). Note that obtaining a sample is not an active method step. In a responder or non-responder infected with HBV, certain biochemical processes will be expressed at certain levels even if one of ordinary skill in the art does not recognize this correlation. Applicant has merely identified the phosphorylation of HBcAgs that are being expressed and the levels of expression. The measuring step is recited at a very high level of generality, and is not limited to any specific type of assay, nor to the use of any particular reagents. The broadest reasonable interpretation of this step, for example, encompasses performing immunoassays with antibodies to the HBcAg particles. These are well-understood, routine and conventional practiced methods. The steps are drawn to measuring the levels of selected genes from a sample and are not considered meaningful limits because it does not narrow the claim so that others are not substantially foreclosed from using the judicial exception. The instant claims are reciting this natural process accompanied by no more than an instruction to apply the natural process using well known and routine techniques (e.g., immunoassays) to carry out the natural process (the levels of expression of selected phosphorylated HBcAgs) and correlating this process to a subject being a responder or non-responder to HBV treatment. Accordingly, claims 1-13 are a recital of a natural process/natural correlation accompanied by additional steps that must be taken to apply the natural process/natural correlation (e.g., the step of taking a sample to test for a naturally occurring correlation). Adding steps to a natural biological process/natural correlation that only recite well-understood, routine, conventional activity previously engaged in by researchers in the field are not sufficient to render the claims patentable. Therefore, the claim as a whole is not drawn to patent eligible subject matter.
Claims 18 is rejected under 35 U.S.C. 101 because the claimed recitation of a use, without setting forth any steps involved in the process, results in an improper definition of a process, i.e., results in a claim which is not a proper process claim under 35 U.S.C. 101. See for example Ex parte Dunki, 153 USPQ 678 (Bd.App. 1967) and Clinical Products, Ltd. v. Brenner, 255 F. Supp. 131, 149 USPQ 475 (D.D.C. 1966).
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.
Claim 18 is rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Regarding claim 18, the claim recites the “use of reagents for detection”, but, since the claim does not set forth any steps involved in the method/process, it is unclear what method/process applicant is intending to encompass. A claim is indefinite where it merely recites a use without any active, positive steps delimiting how this use is actually practiced.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
This application currently names joint inventors. In considering patentability of the claims under 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of 35 U.S.C. 103(c) and potential 35 U.S.C. 102(e), (f) or (g) prior art under 35 U.S.C. 103(a).
Claims 1-17 and 19 are rejected under 35 U.S.C. 103(a) as being unpatentable over Charre et al. “Charre” (Antiviral Research, 2019, 169:1-16, IDS of record dated 02/09/2024) in view of Zhao et al. “Zhao” (Journal of Virology, 2018, 92(13):1-18, IDS of record dated 02/09/2024).
The claims are directed to a method of assessing and monitoring stage or phase of chronic Hepatitis B (HBV) infection or monitoring response to a treatment for chronic HBV in a subject, the
method comprising the steps of: a) performing an assay to detect the presence or level of Hepatitis B core antigen (HBcAg) and phosphorylated Hepatitis B core antigen (P-HBcAg) in at least one sample obtained from a subject diagnosed with chronic HBV or receiving a treatment for chronic HBV, wherein the assay comprises contacting the at least one sample with an antibody that specifically binds to HBcAg and an antibody that specifically binds to P-HBcAg; and b) assessing and monitoring stage or phase of chronic HBV infection or monitoring response to the treatment for chronic HBV based on the presence or level of HBcAg and P-HBcAg in the at least one sample.
Regarding claims 1-14, Charre discloses biomarkers such as serum HBcAg and circulating HBV RNAs as well as non-invasive biomarkers for evaluating intrahepatic covalently closed circular (ccc) DNA abundance and transcriptional activity and the relevance for improving the classification of patients with regards to their natural history; and for evaluating novel compounds to assess target engagement and to define new virological endpoints (Abstract). Charre teaches that “a better appraisal of the risks of viral reactivation in patients who discontinue antiviral treatment or in those undergoing immunosuppressive therapy is much needed. Hence, the development of novel serum biomarkers that better reflect the pool of transcriptionally active cccDNA in the liver than those routinely used for patient monitoring is warranted” (page 1 second column last para.). Charre discloses the monitoring of chronic HBV in subjects comprising the steps of performing an assay to detect the presence or level of HBcAg in samples obtained from subjects, wherein the assay comprises contacting the sample with an antibody that specifically binds to HBcAg; assessing and monitoring stage or phase of HBV infection (section 4 thru 4.1.3 Relevance of these new biomarkers in the classification and monitoring of HBV infection). Charre discloses the method wherein the subject is receiving treatment for chronic HBV and modifying said treatment based on the presence or level of HBcAg (Section 4.2 Evaluation of the efficacy of current treatment, section 4.2.1. Charre discloses how combination trials will require a careful design to ensure accurate evaluation of the antiviral activity of the investigational drugs and their combination. For instance, in add-on trials in NUC (nucleos(t)ide analogs) suppressed patients, the pretreatment period under NUCs will be critical to evaluate the baseline values of each biomarker and their variation during administration of the investigational drugs; and the use of capsid assembly modulator (CAM) for the treatment of chronic HBV (instant claims 1-14, section 5.1. capsid assembly modulators (CAMs). Charre discloses based on the mechanism of action of new drugs being developed, target-specific biomarkers are needed to assess the efficacy of each therapeutic class and to define new endpoints (page 11 section 5).
Charre discloses “in normal conditions, the CTD domain of HBcAg is highly phosphorylated, impairing the packaging of non-specific RNA. However, some conditions might lead to a hypophosphorylated state of the CTD” (page 8 second column) but does not disclose the use of detecting phosphorylated HBcAg (P-HBcAg).
Zhao, however, discloses HBV core proteins are dynamically phosphorylated and dephosphorylated during the viral replication cycle where investigating the mechanism underlying core protein dimer-dimer interfaces. Zhao discloses an immunoblotting assay that can resolve core protein based on its phosphorylation status and demonstrated that core protein is hyperphosphorylated in free dimers and empty capsids (Abstract). Zhao discloses a “novel function of core protein dephosphorylation in HBV replication and the mechanism by which” core protein allosteric modulators “(CpAMs), a class of compounds that are currently in clinical trials for treatment of chronic hepatitis B, induce the assembly of empty capsids” (instant claims 1-4) (page 1 last para.). Zhao discloses that they have developed a western blot assay that allows to conveniently monitor core protein phosphorylation status during viral replication and under antiviral treatment and “that with this technical advantage, we have made several interesting findings and have investigated their biological implications, as summarized in Fig. 9 (instant claims 1-14) (page 14 las para. and pages 16-17 Materials and Methods).
Accordingly, it would have been obvious to one of ordinary skill in the art to generate methods of assessing and monitoring stage or phase of chronic Hepatitis B (HBV) infection or monitoring response to a treatment for chronic HBV in a subject comprising detecting the levels of HBcAg in samples from a subject diagnosed with chronic HBV or receiving treatment for chronic HBV as disclosed by Charre, whereby the method includes detecting the levels of P-HBcAg in samples from a subject diagnosed with chronic HBV or receiving treatment for chronic HBV; and ) assessing and monitoring stage or phase of chronic HBV infection or monitoring response to the treatment for chronic HBV based on the presence or level of HBcAg and P-HBcAg as disclosed by Zhao. One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success given the knowledge that Charre discloses how combination trials will require a careful design to ensure accurate evaluation of the antiviral activity of the investigational drugs and their combination. For instance, in add-on trials in NUC (nucleotide analogs) suppressed patients, the pretreatment period under NUCs will be critical to evaluate the baseline values of each biomarker and their variation during administration of the investigational drugs; and the use of capsid assembly modulator (CAM) for the treatment of chronic HBV (instant claims 1-14, section 5.1. capsid assembly modulators (CAMs); and given the fact that Zhao successfully demonstrates detecting P-HBcAgs to conveniently monitor core protein phosphorylation status during viral replication and under antiviral treatment and “that with this technical advantage, we have made several interesting findings and have investigated their biological implications” (page 14 las para. and pages 16-17 Materials and Methods). Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Regarding claim 15, Charre discloses wherein the nucleic acid is an siRNA (section 5.2).
Regarding claims 16 and 17, Charre discloses the method whereby antibodies are used to bind and detect the HBcAg complex (section 3 and Table 1); and Zhao discloses antibody detection of P-HBcAg (Methods and Materials). With respect to contacting the sample simultaneously or sequentially, in any order is not inventive and considered routine to one of ordinary skill in the art to contact the sample simultaneously or sequentially in any order because a skilled artisan would readily be able to use known molecular techniques to detect HBcAgs in a complex. Moreover, the specification does not discredit or discourage a particular order of contacting the sample to the antibody that would impede the functions of the complex. Furthermore, it has been held that rearranging parts of an invention involves only routine skill in the art. In re Japikse, 86 USPQ 70.
Regarding claim 19, the concept of packaging components into a kit is well known and routine to one of ordinary skill in the art. It would have been obvious to one of ordinary skill in the art at the time the invention was made to package components into a kit given the knowledge that Charre in view of Zhao discloses the components used in their methods for detecting the presence, level or status of HBcAg and P-HBcAg. One of ordinary skill in the art would be motivated to do this for commercial exploitation of the invention and to provide convenience for the end user.
Therefore, the claimed invention would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Barry Chestnut whose telephone number is (571)270-3546. The examiner can normally be reached on M-Th 8:00 to 4:00.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Thomas Visone can be reached on 571-270-0684. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from the Patent Application Information Retrieval (PAIR) system. Status information for published applications may be obtained from either Private PAIR or Public PAIR. Status information for unpublished applications is available through Private PAIR only. For more information about the PAIR system, see http://pair-direct.uspto.gov. Should you have questions on access to the Private PAIR system, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative or access to the automated information system, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/BARRY A CHESTNUT/Primary Examiner, Art Unit 1672