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 .
Information Disclosure Statement
Information Disclosure Statement has not been provided.
The listing of references in the specification is not a proper information disclosure statement. 37 CFR 1.98(b) requires a list of all patents, publications, or other information submitted for consideration by the Office, and MPEP § 609.04(a) states, "the list may not be incorporated into the specification but must be submitted in a separate paper." Therefore, unless the references have been cited by the examiner on form PTO-892, they have not been considered.
Election/Restrictions
Claims 5 and 17-30 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species and inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on September 11, 2025. Applicant elected a Cyclin D1-CDK4 pathway and Cyclin D1 oncoprotein.
Claims 2-3 recite E2F1 target gene, which is part of nonelected 6-RB1-E2F1 pathway. Therefore, claims 2-3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected species of 6-RB1-E2F1 pathway.
Claims 1, 4, and 6-16 are examined herein.
Drawings
The drawings are objected to because:
Figures 2D, 7B, 8A, 8B, and 8C do not have legible legends: both -1/+1 and -2/+2 fields have similar intensities;
Figures 2D and 6C do not have legible legends; and intensities in the figures are too dark;
Figures 10F, 13A, and 13C have insufficient image quality.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Claim Objections
Claims 1, 15, and 16 are objected to because:
Claim 1 contains abbreviations CDK4, ATF3, and 6-RB1-E2Fl.
Claim 15 contains abbreviation TALEN.
Claim 16 contains abbreviations CB-5083, NMS-873, NMS-859, DBeQ, MSC1094308, ML240, p97-IN-l, VCP/p97 inhibitor-I, ML241 hydrochloride, and UPCDC-30245.
These should be completely spelled out in its first occurrence.
Appropriate correction is required.
Claim Interpretation
Claim 1 preamble recites a method “of measuring sensitivity of a subject to p97 inhibition”. The normal purpose of a claim preamble is to recite the purpose or intended use of the claimed invention. Such statements merely define the context in which the invention operates and usually will not limit the scope of the claim (MPEP 2111.02 and DeGeorge v. Bernier, Fed. Cir. 1985, 226 USPQ 758, 761 n.3).
In the instant case, the statement in the preamble does not provide antecedent basis for terms in the body of the claim, and is not essential to understand the limitations or terms in the body of the claim. The claim does not include, for example, active method steps in which the subject sensitivity to p97 inhibition is measured; therefore, the clause is not considered to further limit the method defined by the claim and has not been given weight in construing the claims. The body of the claim only recites expression profiles of the oncoproteins.
Claim 1 recites “wherein the measured expression profile of the oncoproteins differs from a normal expression profile from a healthy subject”; and
Claim 6 recites “wherein the cancer or a symptom thereof is reduced after the administering.”
It is noted that such statements do not recite any additional active method steps, but simply express the intended result of the process steps positively recited. Therefore, the “wherein” statements are not considered to further limit the method defined by the claim and have not been given weight in construing the claims. See MPEP 2111.04.
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, and 6-16 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; and 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.
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.
State of the prior art & level of predictability in the art.
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 level of one of ordinary skill is high with an ordinary practitioner possessing a PhD and related post-doctoral research experience.
Amount of direction and example provided by the inventor.
The specification is silent with respect to examples that disclose methods for measuring sensitivity of a 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.
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. Paragraph [0110] merely recites claim 1 without providing any additional information.
Examples provided in the specification also fail to disclose the methods for measuring sensitivity of a subject to p97 inhibition, as they focus on other aspects of the invention:
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]);
The final, Example 5 discloses that p97 inhibition promotes the downregulation of cell cycle oncoproteins, but no sensitivity measurements are disclosed ([0175]).
Additionally, claim 1 recites “methods for measuring sensitivity of a subject to p97 inhibition”, where a biological sample from a subject is used to measure expression profiles of the oncoproteins. 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 dependent claims 6-16 are related to administering an agent to the subject.
Finally, dependent claims 6-16 are not linked in any way to the “sensitivity of a subject to p97 inhibition” or the expression profiles of the oncoproteins.
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.
In summary, the originally filed specification lacks direction or guidance with regard to how to use the method of claim 1 and its purpose in instant invention.
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 T ALEN 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.
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.
Claim 1, 4, and 6-16 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 method of measuring sensitivity of a subject to p97 inhibition”. It is unclear what method steps are responsible for measuring sensitivity of a subject to p97 inhibition, as described in the claim interpretation section above. Claim 1 and its dependent claims fail to recite any steps for measuring sensitivity of a subject to p97 inhibition or how measuring an expression profile of oncoproteins is related to p97 inhibition.
Finally, claim 1 recites measuring an expression profile of oncoproteins. The results of this measurement are never used in any dependent claims. The purpose of measuring an expression profile of oncoproteins is unclear. Dependent claims 4 and 6-16 fail to clarify the matter.
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, and 6 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. These additional steps of “identifying”, “obtaining” and “measuring” are an insignificant extra-solution activity that amounts to mere data gathering necessary to apply the judicial exception.
The claim does not recite any additional steps, such as starting an appropriate treatment. When considering the elements in combination, the claim as a whole does not integrate the recited exceptions into a practical application. Additional elements of measuring the expression profiles of oncoproteins are considered insignificant extra-solution activities, because they are recited at a high level of generality ([0048]), and have been recognized as routine laboratory techniques.
The dependent claims 4 and 6 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 recites administering an effective amount of an agent that inhibits p97 in the subject. Although this limitation indicates that a treatment is to be administered, it does not provide any information as to how the subject is to be treated or what the treatment is, but instead covers any possible treatment that a medical professional decides to administer to the subject. As such, there are no meaningful constraints on the administering step such that the particular treatment consideration would apply because it is not limited to any particular manner or type of treatment. See MPEP 2106.04(d)(2).
Therefore, claim 6 limitation of administering an effective amount of an agent that inhibits p97 in the subject fails to meaningfully limit the claim because it does not require any particular application of the abstract idea and therefore amounts only to a generic instruction to “apply” the exception or to a mere indication of the field of use or technological environment in which the abstract idea is performed.
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, and 6 are ineligible under 35 U.S.C. 101.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1 and 4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Kim et al. (J Cell Physiol. 2009 Aug;220(2):292-6).
Regarding claim 1, Kim teaches that cyclin D1 is frequently overexpressed in cancers (Abstract). The term overexpression is used in the art with an implied reference to non-overexpressed or basal conditions taking place in non-cancer cells. Overexpression is determined using biological samples obtained from human subjects (pg. 293, col. 1, par. 2).
Absent any limitations that would clearly require measuring sensitivity of a subject to p97 inhibition, the reference reads on the claim when given its broadest reasonable interpretation.
Regarding claim 4, Kim teaches cyclin D1 overexpression in mantle cell lymphoma (pg. 293, col. 1, par. 2), meeting the limitation of claim 4 reciting a lymphoma.
Subject Matter Free of the Prior Art
Claims 6-16 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
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