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
Claims 1, 4, and 6-16 were pending. Claim 1 is amended. Claim 31 is added.
Claims 1, 4, 6-16, and 31 are examined herein.
Claim Objections
Claim 16 is objected to because:
Claim 16 contains abbreviation p97-IN-1. It should be spelled out using a proper IUPAC name as used in scientific literature and chemical databases. A chemical formula used in the amended claim does not uniquely identify the molecule.
Appropriate correction is required.
Withdrawn Rejections
The objection to the drawings is withdrawn in view of submitted drawings in color.
The objection to claims 1 and 15 is withdrawn in view of claims amendments.
The rejection of claims 1 and 6-16 under 112(b) is withdrawn in view of claim 1 amendments.
The rejection of claims 1 and 4 under 102 is withdrawn in view of claim 1 amendments.
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.
Claims 1, 4, 6-16, and 31 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 1 recites a method of measuring sensitivity of a subject to p97 inhibition, the
method comprising: identifying a subject having a cancer, or a symptom thereof; measuring an expression profile of oncoproteins in a biological sample obtained
from the subject, wherein the measured expression profile of the oncoproteins differs from a normal expression profile from a healthy subject; wherein the oncoproteins comprise cell cycle oncoproteins or oncoproteins of a Cyclin Dl-CDK4 or 6-RB1-E2Fl pathway; and wherein the oncoproteins of the Cyclin Dl-CDK4 or 6-RB1-E2Fl pathway comprise Cyclin DI, CDK4, or ATF3; comparing the measured expression profile of the oncoproteins to an expression
profile from a subject without cancer; identifying the subject as having sensitivity to p97 inhibition based on the comparing, wherein sensitivity to p97 inhibition is indicated by a different expression status of one or more of the oncoproteins relative to the expression profile from the subject without cancer; wherein sensitivity to p97 inhibition indicates a reduction in cancer or cancer symptoms in the subject in response to p97 inhibitor treatment; administering to the subject having the sensitivity to p97 inhibition a pharmaceutical agent that inhibits p97 in the subject.
As recited, the invention is directed to measuring sensitivity of a subject to p97 inhibition. The specification discloses various embodiments of the invention primarily focused on inhibiting p97 for treatment of various cancers. Measuring sensitivity of a subject to p97 inhibition is not disclosed.
The prior art is silent on measuring sensitivity of a subject to p97 inhibition using measuring expression profiles of the oncogenic proteins. The art of cancer treatment is highly unpredictable.
The specification is silent on disclosing evidence or methods results of measuring sensitivity of any subject to p97 inhibition. The sensitivity as defined in the specification “"sensitivity to p97 inhibition" or "susceptibility to p97 inhibition" can indicate a reduction in cancer or cancer symptoms in a subject in response to p97 inhibitor treatment” ([0049]) fails to clarify the problem as there is no link in the disclosure between this definition and the expression profiles of the oncoproteins. As such, Applicant postulates without evidence that sensitivity to p97 inhibition is indicated by a different expression status of one or more of the oncoproteins relative to the expression profile from the subject without cancer.
Another passage from the specification says: “Described herein are methods of treatment of cancer. In some embodiments, the sensitivity to p97 inhibition in a subject in need of treatment for cancer is determined” ([0100]), however, none of the following paragraphs of the specification disclose how the sensitivity to p97 inhibition in a subject in need of treatment for cancer is actually determined.
Examples provided in the specification also fail to disclose the methods for measuring sensitivity of a subject to p97 inhibition. They focus on other aspects of the invention and fail to measure p97 inhibition:
Example 1 discloses proteomic profiling using a cell line ([0162]);
Example 2 discloses comparative proteomics ([0165]);
Example 3 discloses identification of specific protein markers of p97 inhibition, but no sensitivity measurements are disclosed ([0170]);
Example 4 discloses p97 inhibition blocking E2Fl-mediated transcription via downregulation of the CCNDCDK4/6 complex, but no sensitivity measurements are disclosed ([0171]) and link is established between the p97 inhibition blocking E2Fl-mediated transcription and potential effects of disclosed cancer treatments;
Example 5 discloses that p97 inhibition promotes the downregulation of cell cycle oncoproteins, but no sensitivity measurements are disclosed ([0175]) and link p97 inhibition - cancer treatment is established.
Additionally, the specification fails to disclose how the sensitivity of the entire subject to p97 inhibition is derived from the measured expression profiles of the oncoproteins in the subject’s sample. This is a key omission because administering p97 inhibitor treatment is directly linked to this sensitivity.
Finally, claim 1 recites “sensitivity to p97 inhibition is indicated by a different expression status of one or more of the oncoproteins relative to the expression profile from the subject without cancer”. However, the specification fails to disclose any evidence for supporting the link between the sensitivity to p97 inhibition and a different expression status of one or more of the oncoproteins relative to the expression profile from the subject without cancer.
Another aspect of failing to comply with the written description requirement is the disclosure of data obtained using only cell lines: HEK293, HT29, U2OS, and HCT116 cells. The specification fails to disclose any data on subjects having a cancer, or a symptom thereof in respect to observed reduction of the cancer or a symptom thereof. In fact, no actual subjects have been involved in disclosed experiments and no actual treatments have been performed on these subjects. It is known in the art of cancer treatment that there is a big gap between cell culture experiments (performed primarily on HCT116 cells) and actual subject treatments using p97 inhibitors.
Dependent claims 13 and 14 recite the p97 binding antagonist is an antibody against p97 or a fragment of p97, and the antibody is a monoclonal, polyclonal or an antibody fragment selected from the group consisting of Fab, Fab'-SH, Fv, scFv, and (Fab')2 fragments.
The prior art and the specification are silent on using antibodies with specificity toward an intracellular enzyme target in cancer cells or cancer subjects.
Finally, claim 15 recites the genetic tool is selected from the group consisting of a CRISPR/Cas9 system, a zinc finger nuclease system, a TALEN system, a homing endonucleases system, and a meganuclease system. The recited genetic tools are known for their ability to completely remove or inactivate their target genes. However, p97 is an essential cellular protein and the specification fails to disclose how to target the genetic tools and inhibit p97 in the subject without completely destroying its essential functions.
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.
Claim 4 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 4 recites the cancer comprises a blood tumor, a solid tumor, a lymphoma, a myeloma, acute myeloid leukemia (AML), esophageal cancer, colon cancer, uterine cancer, or myelodysplastic syndrome (MDS). The claim is indefinite because it uses the open “comprising” language.
Claim 4 recites the cancer comprises a blood tumor, a lymphoma, a myeloma, acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). It is unclear what kinds of cancers are actually claimed because the recited cancers overlap. For example, blood tumors, also known as blood cancers, include lymphoma and leukemia separately recited in the claim. A myelodysplastic syndrome (MDS) is not one specific kind of cancer, but a group of blood cancers in which blood cells in the bone marrow do not mature.
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, 4, 6-16, and 31 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a naturally occurring correlation, without significantly more.
Claim 1 is directed to a process, which belongs to the four statutory categories. The claim is related to a method of establishing a relationship between expression profiles of oncoproteins of a subject having a cancer and a healthy subject. This relationship is categorized as a naturally occurring correlation, and therefore it is a judicial exception.
The claim also recites steps of identifying a subject having a cancer, or a symptom thereof, obtaining a sample from the subject, and measuring the expression profile of oncoproteins. The additional steps of “obtaining” and “measuring” is an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
The additional steps of “identifying” and “comparing” amounts to making a conclusion based on the results of expression profile measurements. These steps are mental processes, performed in the human mind and considered an observation, evaluation, and/or a judgement. The limitations of “identifying” and “comparing” fall into the mental process groupings of abstract ideas and therefore is a judicial exception.
The claim also recites administering to the subject having the sensitivity to p97 inhibition a pharmaceutical agent that inhibits p97 in the subject. Although the additional step of treating the patient indicates that a treatment is to be administered, it does not provide any specific information as to how the patient is to be treated. Applicant fails to recite or disclose any known pharmaceutical agents suitable for treating cancers sensitive to p97 inhibition. Without known medications the administering step of claim 1 fails to integrate the judicial exceptions into a practical application. A practical application cannot rely on a pharmaceutical agent that has not been proven to be a medication for treating cancers sensitive to p97 inhibition.
Therefore, the limitation of treating thus fails to meaningfully limit the claim.
Accordingly, the limitation of administering does not integrate the recited judicial exception into a practical application and the claims are therefore directed to the judicial exception.
Claim 1 as a whole does not amount to significantly more than the judicial exception of a law of nature or a naturally occurring correlation. The concept of measuring expression profile of oncoproteins is well-understood, routine, and conventional. For example, Kim et al. (J Cell Physiol. 2009 Aug;220(2):292-6)) teach that cyclin D1 is frequently overexpressed in cancers (Abstract). Overexpression is determined using biological samples obtained from human subjects (pg. 293, col. 1, par. 2).
The dependent claims 4, 6-16, and 31 fail to add additional elements, or combination of additional elements, that contribute to an inventive concept to the claim. Claim 4 recites various cancers, which do not share any common origin or biochemistry. Claim 6 does not recite any method steps.
Therefore, the claims 1, 4, and 6 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.
For these reasons, claims 1, 4, 6-16, and 31 are ineligible under 35 U.S.C. 101.
Response to Arguments
Applicant’s arguments filed May 11, 2026 have been fully considered.
Claims 1, 4, and 6-16 were rejected under 35 U.S.C. § 112(a) for failure to comply with the written description requirement.
Applicant argues that “that there is no per se requirement that there be a working example of the claimed method for there to be adequate written description support” (pg. 8, last par. – pg. 9, par. 1). The argument is not persuasive because the rejection under 35 U.S.C. § 112(a) was not based on the absence of working examples alone. Working examples is just one of the ways to demonstrate adequate written description support and possession of the claimed invention. In the instant case Applicant failed to use working examples for this purpose.
Applicant argues that “The specification repeatedly and expressly describes the subject matter recited in the claims” (pg. 9, par. 2). Specifically, Applicant argues:
“The Summary states that some embodiments relate to "methods of measuring sensitivity of a subject to p97 inhibition,"” (id.). The summary statement is too general and not sufficient to demonstrate that Applicant had possession of the claimed invention at the time the application was originally filed;
“The specification further identifies the same classes of oncoproteins now recited in the amended claim” (id.). The classes of oncoproteins do not overcome the rejection stating “Measuring sensitivity of a subject to p97 inhibition is not disclosed” (OA, 10 February 2026; pg. 5, par. 2);
“Paragraph [0048] of the specification states that "measuring" can include assessing the expression profile of genes, including genes for oncoproteins, in a subject having cancer and healthy subjects, and can further include comparing the expression profile of genes or protein expression levels of oncoproteins between subjects having cancer and healthy subjects” (pg. 9, par. 3). The argument fails to disclose how measuring sensitivity of a subject to p97 inhibition was achieved;
“Paragraph [0050] of the specification further identifies suitable biological samples, including blood, tumor biopsy, cerebrospinal fluid, saliva, urine, and bone marrow” (id.). The argument is not persuasive because there is no p97 inhibition in this disclosure;
“Paragraph [0052] of the specification states that "a different expression status between the measured expression of the oncoproteins and normal expression from a healthy subject can include overexpression, under expression, gain of function mutations, or loss of function mutations." (pg. 10, par. 1). The argument is not persuasive because there is no evidence of p97 inhibition in this disclosure;
“In addition, the specification expressly defines sensitivity. Paragraph [0049] of the specification states that "sensitivity to p97 inhibition" can indicate a reduction in cancer or cancer symptoms in a subject in response to p97 inhibitor treatment” (pg. 10, par. 2). The argument is not persuasive because defining sensitivity does not replace providing evidence for p97 inhibition and the reduction in cancer or cancer symptoms due to "sensitivity to p97 inhibition" is not disclosed. Additionally, “can indicate a reduction in cancer” is not an indication of a possession because it does not provide evidence that Applicant established a functional link between sensitivity to p97 inhibition and a reduction in cancer or cancer symptoms in a subject in response to p97 inhibitor treatment;
“Paragraph [0094] of the specification directly rebuts the Examiner's contention that the specification fails to connect oncoprotein measurements with the effect of treatment in a subject. The specification states that assessing the effect of a pharmaceutical agent on a subject can include determining oncoprotein expression levels from a patient sample following administration of the agent, and measuring reduction of cancer or symptoms in the subject following administration of the pharmaceutical agent” (pg. 10, last par.). The argument is not persuasive because Applicant fails to disclose evidence actually connecting oncoprotein measurements with the effect of treatment in a subject. Moreover, there is no evidence of any treatment administered, any treatment results reported, and no disclosure of any known pharmaceutical agents capable of p97 inhibition and cancer treatment that can be readily prescribed by a medical practitioner;
“The Examiner’s rejection for obtaining data from cell lines and not in clinical subjects is improper, written description does not require a clinical trial or human efficacy dataset to support possession of a claimed diagnostic-and-treatment framework, particularly where, as here, the specification expressly describes the method, defines the claimed sensitivity concept, and identifies the comparative expression changes relevant to that concept. See M.P.E.P. § 2163.02” (pg. 11, par. 1). The argument is not persuasive because cited section of MPEP does not discuss clinical trial or human efficacy as Applicant argues. This section provides an objective standard for determining compliance with the written description requirement - "does the description clearly allow persons of ordinary skill in the art to recognize that he or she invented what is claimed." In the absence of any p97 inhibition evidence, data, or measurements in the specification a person of ordinary skill in the art cannot reasonably conclude that Applicant was in possession of this invention;
“The law does not require that every claimed medical method be accompanied by a completed human clinical study in order to satisfy§ 112(a)” (pg. 11, par. 1). The argument is not persuasive because the rejection does not relay solely on the lack of human clinical studies as Applicant alleges. However, since claim 1 recites “measuring sensitivity of a subject”, the specification has to provide some evidence for such inhibition in a subject. The specification as filed does not have any evidence for measured sensitivity to p97 inhibition in samples taken from real subjects. Applicant fails to fill the gap in the disclosure between cell lines and real subjects as far as administering treatments and reduction of cancer is concerned.
Claims 1, 4, and 6-16 were rejected under 35 U.S.C. § 112(b) as being indefinite.
Claim 1 amendments are sufficient to overcome the rejection; therefore, the rejection of claims 1 and 6-16 under 112(b) is withdrawn. However, claim 4 is still rejected under 112(b). The claim is indefinite because it uses the open “comprising” language. Applicant failed to address this rejection.
Claims 1, 4, and 6 are rejected under 35 U.S.C. § 101 as being directed to a naturally occurring correlation, without significantly more.
Applicant disagrees (pg. 13, par. 1 – pg. 14, par. 1). Specifically, Applicant argues that “As amended, claim 1 satisfies that standard” concluding that “That treatment step is affirmative, concrete, and meaningfully connected to the preceding measurement and comparison steps. The claim therefore does not merely recite a natural correlation plus insignificant post-solution activity; instead, it integrates any alleged exception into a specific cancer-treatment application” (pg. 14, par. 2). The argument is not persuasive because Applicant fails to recite or disclose any known pharmaceutical agents capable of treating cancers sensitive to p97 inhibition. Without known medications the administering step of claim 1 fails to integrate the judicial exceptions into a practical application. A practical application cannot rely on a pharmaceutical agent that has not been proven to be a medication for treating cancers sensitive to p97 inhibition.
Claims 1 and 4 are rejected under 35 U.S.C. § 102(a)(l) as being anticipated by Kim.
Applicant argues that “Kim does not disclose, expressly or inherently, the methods as recited in the amended claims” (pg. 15, last par.). The argument is persuasive; therefore, the rejection of claims 1 and 4 under 102 is withdrawn.
Subject Matter Free of the Prior Art
Claims 1, 4, 6-16, and 31 are free of the prior art.
The prior art neither teaches nor suggests combining a method of measuring sensitivity of a subject to p97 inhibition by measuring an expression profile of oncoproteins in a biological sample with administering various p97 inhibitors to cancer subjects.
The closest prior art teaches:
Youn et al. (KR20210094356A) - personalized medicine approach for development of a diagnostic marker capable of diagnosing radiation-resistant cancer cells, and, in particular, completed the present invention as a result of repeated research and experiments to discover a diagnostic marker capable of diagnosing radiation-resistant melanoma ([0006]), specifically a method for providing information for diagnosing radiation resistance of a cancer patient is provided, comprising: measuring an expression level of mRNA or protein of one or more genes selected from the group consisting of CASP1, CCND1, ENO2, HSPA1A, NGFR, OAS1, OAS2, and SRGN from a biological sample; and comparing the measured expression level of the mRNA or protein with an expression level of the mRNA or protein measured in a control sample ([0017]). The reference fails to teach sensitivity to p97 inhibition and administering p97 inhibitors to a subject;
Roux et al. (Sci Transl Med. 2021 Mar 31;13(587): eabg1168) – identified valosin-containing protein (VCP), which is another name for p97 as a target for CB-5339 small molecule inhibitor (Abstract). The reference fails to teach sensitivity to p97 inhibition and measuring expression profiles of oncoproteins;
Desdicioglu et al. (Mol Biol Rep. 2021 Mar;48(3):2163-2171) - targeting of p97/VCP with its specific inhibitors or siRNA’s (siVCP) in cancer therapy (Abstract). The reference fails to teach sensitivity to p97 inhibition and measuring expression profiles of oncoproteins;
Zhao et al. (Am J Transl Res. 2020 Jun 15;12(6):2956-2967) - p97 antitumor ability of CB-5083, an oral inhibitor of P97, in osteosarcoma. The reference fails to teach sensitivity to p97 inhibition and measuring expression profiles of oncoproteins.
Conclusion
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). 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 date of this final action.
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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