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 .
Response to Amendment/Status of Claims
Receipt of Arguments/Remarks filed on 09/19/2025 is acknowledged. Claims 4,6-10 and 25-33 were/stand cancelled. Claims 34-36 are new. Claims 1-3 were amended. Claims 1-3,5,12-24 and 34-36 are pending and under examination.
Claims 21-24 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 06/26/2024.
Response to Arguments
Applicant’s arguments and amendments, see page 7, filed 09/19/2025, with respect to the objection to the drawings have been fully considered and are persuasive due to the replacement drawings correcting the issues. The objection to Figures 2,3,7,8 and 18 has been withdrawn.
Applicant’s arguments and amendments, see page 12, filed 09/19/2025, with respect to the Non-statutory Double Patenting Rejection of claims 1-3,5 and 12-16 over claims 25-26 of Application No. 17/369,032 have been fully considered and are persuasive do to the amendments to the instant claims reciting that the UBE2K inhibitor is a nucleic acid inhibitor as well as the cancelation of claims 25-26 of Application No.
17/369,032. The Non-statutory Double Patenting Rejection of claims 1-3,5 and 12-16 has been withdrawn.
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 1-3,5,12-20 and 34-36 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.
The term “preferentially” in claims 1-3 is a relative term which renders the claim indefinite. The term “preferentially” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. Claims 1-3 recite wherein the UBE2K inhibitor preferentially inhibits UBE2K as compared to other E2 proteins, but it is unclear of what this means. Does this mean the inhibitor binds to UBE2K more than any other E2 protein, or what is the degree of binding to UBE2K for the inhibitor to be considered to preferentially inhibit UBE2K compared to other proteins. While page 19 describes that the UBE2K specific inhibitor preferentially inhibits UBE2K as compared to one or more different E2 proteins by at least 5-fold…. Or at least 100-fold, this is not a definition of the term and cannot be read into the claim, and therefore the claim is indefinite. Claims 5,12-20 and 34-36 depend on claim 1 and do not correct the issue and are included in this rejection.
Response to Arguments
No response has been provided regarding the 35 U.S.C. 112(b) rejection of claims 1-3,5,7 and 12-20 found on page 27 of the office action dated 03/19/2025 and no amendments were made to correct the issue, and therefore the rejection is maintained.
Written Description Rejection
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 1-3,5,12-20 and 34-36 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.
Claims 1-3,5 and 12-20 encompass a large genera of Ubiquitin Conjugating Enzyme E2 K (UBE2K) nucleic acid inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2, that preferentially inhibits UBE2K as compared to other E2 proteins and that treat cancer, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject and claims 1-3,5 and 17-20 encompass treating a large genus of cancers. Claims 13-16 recite the specific solid tumors and leukemia. Claims 34-36 recite nucleic acid inhibitors comprising an antisense nucleic acid molecule, double stranded nucleic acid molecule, wherein the double stranded nucleic acid molecule comprises a double stranded RNA selected from the group consisting of an siRNA, shRNA and a dicer substrate siRNA (DsiRNA), however still encompass a large genus of nucleic acid inhibitors that have various sequences and structures.
The state of the art only teaches a few known UBE2K inhibitors and their effect on cancer before the effective filing date, and the state of the art is silent regarding UBE2K inhibitors that preferentially inhibit UBE2K as compared to other E2 proteins.
The nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 and preferentially inhibits UBE2K as compared to other E2 proteins and treats a large genus of cancer, reduces proliferation of a cancer cell and induces cell death of a cancer cell in a human subject reads on a large number of nucleic acid compounds, including antisense oligonucleotides, anti-miRs, antagomirs, aptamers, ribozymes, CRISPR-Cas complex and RNAi. Each nucleic acid compound has a different structure and/or function. Jarald et al. (African Journal of Biotechnology Vol. 3, Published Dec 2004, pages 662-666) teach a variety of inhibitory nucleic acid drugs with different target sites and mechanisms of action, in which nucleic acid drugs that can be subdivide into 5 classes based upon their target site and mechanism of action, and include aptamers, antisense oligonucleotide, ribozyme nucleic acids, RNA interference, and anti-gene nucleic acids (page 663, top left). KR 20150016816, hereinafter “Gwangju” (Published 3 June 2015), and cited on an IDS teaches PC3 cells transfected with UbbsiRNA were subcutaneously administered to mouse xenograft models and that the growth of PC3 cell-derived tumors was inhibited by UBB knockdown, resulting in about 40% reduction in tumor volume and weight [0080]. Gwangju teaches the amount of Ub-binding enzyme, e.g., Ube2K/E2-25K to Ub was reduced by Ubb siRNA treatment [0069], and proliferation of PC3 and HepG2 hepatocellular carcinoma cells was inhibited using siRNA [0071-0072]. However, Gwangju does not teach that the UbbsiR preferentially inhibits UBE2K as compared to other E2 proteins.
When claims 1-3,5,12-20 and 34-36 are analyzed in light of the specification, the instant invention encompasses a large genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2, that preferentially inhibits UBE2K as compared to other E2 proteins and that treat a genus of cancers, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject. The specification discloses the human UEB2K nucleic acid sequence is provided as SEQ ID NO: 2 (page 18, lines 1-2). The specification contemplates that the present disclosure includes a nucleic acid (e.g. antisense, siRNA, shRNA, dsiRNA, etc.) that partially or fully inhibits the enzyme by reducing the expression and/or activity of the enzyme (page 19). The specification contemplates that the UBE2K inhibitor can act by any mechanism, by inhibiting the expression at the RNA or protein level or inhibiting the activity of UBE2K, and in some embodiments is a specific inhibitor of UBE2K and does not substantially reduce the expression or activity of other polypeptides other than UBE2K (page 19). The specification contemplates that nucleic acid UBE2K inhibitors may be single or double stranded nucleic acids having a complementary region of at least 15 nucleotides in length that are complementary to a target sequence in a cell (page 19). Single stranded nucleic acid therapeutics are described on page 25, including antisense nucleic acids, and double stranded nucleic acids such as dsRNA, siRNA and iRNA agents are described on page 26-27. However, the specification fails to identify that these disclosed nucleic acid UBE2K inhibitors preferentially inhibit UBE2K compared to other E2 proteins and results in treating a genus of cancers in a subject and therefore the structure required for the function of preferentially inhibiting UBE2K compared to other E2 proteins and treating cancer is not shown.
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. The examples disclose that UBE2K was transiently knocked down using siRNA in Miapaca2, HepG2, SKHEP1, Hep3B, MDAMB231, SKBR3, T47D and BT549 cells (Example 2, page 63), and that UBE2K siRNA mediated knockdown resulted in a 50% decrease in cell number in Miapaca2 pancreatic cancer cells, 30% decrease in cell number in SKHEP1 and HepG2 hepatocellular carcinoma cells, and no effect of the siRNA in the remaining 5 cancer cell lines (page 63; Table 4 page 64). Example 5, pages 68-69 disclose UBE2K knock-down with shRNA. However, no sequences of the siRNAs or shRNA for UBE2K knock-down are disclosed. The number of species disclosed by complete structure is not sufficient to provide written description support for the broad genus of nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins and that treat a genus of cancers, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject.
In the instant case, there are no nucleic acid UBE2K inhibitors whose complete structure is disclosed. While the state of the art teaches the specific siRNA of SEQ ID NO: 1 that inhibits Ubb and reduces UBE2K to treat cancer (Gwangja, paragraph 0042), these UBE2K inhibitors do not appear to preferentially inhibit UBE2K as compared to other E2 proteins. There is a lack of a complete or partial structure for the claimed genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 with the function of preferentially inhibiting UBE2K as compared to other E2 proteins and that treat cancer, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject. The specification fails to identify the core structure of the nucleic acid inhibitor that is complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 that is required to achieve the claimed function. No other species of UBE2K nucleic acid inhibitors are identified or described by the state of the art or specification, such as aptamers, ribozymes, miRNA to provide a representative number of UBE2K nucleic acid inhibitors for the genus. One of ordinary skill in the art could make siRNA and antisense oligonucleotides by aligning an oligomer to a region of UBE2K nucleotides of SEQ ID NO: 2 and reduce expression of the sequence, however this does not provide support that these sequences would preferentially inhibit UBE2K compared to other E2 proteins and result in the functions recited in the instant claims regarding treating, reducing proliferation of, and inducing death of a genus of cancer cells in a subject and does not provide written support for aptamers, ribozymes, or miRNAs encompassed by the genus of nucleic acid UBE2K inhibitors.
While the genus encompasses a large number of nucleic acid variants and molecules that have the same activity of preferentially inhibiting UBE2K, thereby treating cancer, reducing proliferation of cancer cells and inducing death of cancer cells in a subject, UBE2K inhibitory nucleic acid compounds that preferentially inhibits UBE2K as compared to other E2 proteins in kind and the genus encompass a large number of variants and molecules that have a different structure, and the specification does not describe an essential structure of a representative number of species of the large genus of UBE2K nucleic acid inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 that preferentially inhibits UBE2K as compared to other E2 proteins and that treat a genus of cancer, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject. The specification does not provide description for which species of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 within the broad genus would or would not result in preferentially inhibiting UBE2K as compared to other E2 proteins, and treating cancer, reducing proliferation of a cancer cell or inducing death of a cancer cell in a subject. The genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 encompass many species including antisense oligonucleotides, anti-miRs, antagomirs, aptamers, ribozymes, CRISPR-Cas complex and RNAi, and there is significant variation in the structure and function among the species encompassed by the instant claims.
Regarding the wherein clause reciting the sequence of the human UBE2K mRNA transcript in the amended claims, MPEP 2163 says “For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional.” See Amgen Inc. v. Sanofi 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017) cited in MPEP 2163. Therefore, the disclosure of SEQ ID NO: 2 as the human UBE2K nucleic acid sequence that the nucleic acid inhibitor is complementary to does not provide adequate written description of a nucleic acid inhibitor of UBE2K that preferentially inhibits UBE2K as compared to other E2 proteins and results in treating cancer.
Therefore, the number of species disclosed by complete structure is not sufficient to provide written description support for the entire broad genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 that preferentially inhibits UBE2K as compared to other E2 proteins and that results in treating a genus of cancer, reducing proliferation of a cancer cell or inducing death of a cancer cell in a subject in need thereof.
Next, then, it is determined whether a representative number of species have been sufficiently described by other relevant identifying characteristics (i.e., other than nucleotide sequence), specific features and functional attributes that would distinguish different members of the claimed genus. In the instant case, the functional characteristics in claims 1-3 (preferentially inhibits UBE2K as compared to other E2 proteins, treating cancer, reducing proliferation of a cancer cell and inducing death of a cancer cell in a subject) are not coupled with a known structure. The specification fails to identify a core structure of the nucleic acid inhibitor complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 necessary for preferentially inhibiting UBE2K as compared to other E2 proteins, for treating cancer, reducing proliferation of a cancer cell and inducing death of a cancer cell in a subject as well as a partial structure, physical or chemical property, or functional characteristic coupled with a structure/function relationship responsible for preferentially inhibiting UBE2K as compared to other E2 proteins and for treating cancer, reducing proliferation of a cancer cell and inducing death of a cancer cell in a subject to demonstrate possession of the full invention as claimed at the time of filing.
Applicant’s attention is directed to the Guidelines for the Examination of Patent Applications Under the 35 U.S.C. 112(a) or Pre-AIA 35 U.S.C. 112, first paragraph, "Written Description" Requirement (MPEP2163).
In conclusion, Applicants disclosure of the target human UBE2K mRNA transcript of SEQ ID NO: 2 that the nucleic acid UBE2K inhibitor is complementary to is not deemed sufficient to reasonably convey to one skilled in the art that the instant disclosure was in possession of the claimed broad genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 with the function of preferentially inhibiting UBE2K as compared to other E2 proteins and that treats a genus of cancer, reduces proliferation of a cancer cell or induces death in a cancer cell in a subject in need thereof at the time the application was filed. Thus, it is concluded that the written description requirement is not satisfied for the claimed genus.
Response to Arguments
Applicant's arguments, filed 09/19/2025, have been fully considered but they are not persuasive.
Applicant cites MPEP 2163 II A3(a)(ii) on page 8, and restates what amended claims 1-3 recite, which is that the UBE2K inhibitor is a nucleic acid inhibitor that is complementary to a human UBE2K mRNA transcript encoded by the nucleic acid sequence of SEQ ID NO: 2. Applicant argues on page 9 that the specification describes a broad range of nucleic acid UBE2K inhibitors include single stranded nucleic acids such as antisense nucleic acids, double stranded nucleic acids such as double stranded RNA molecules, e.g., siRNAs (pages 20-27). Applicant argues that the specification teaches that nucleic acid inhibitors include both single and double stranded nucleic acids (i.e., nucleic acids having a complementarity region of at least 15 nucleotides in length) that are complementary to a target sequence in a cell (page 20, lines 23-26), and the specification teaches that antisense nucleic acid therapeutic agents are single stranded nucleic acids, typically about 16-30 nt in length, and are complementary to a target nucleic acid sequence in a target cell (page 25, lines 18-20) and teaches that antisense RNA molecule may have about 15-30 nt that are complementary to the target mRNA and the antisense RNA molecule may have a sequence of at least 15,16,17,18,19,20 or more contiguous nucleotides that are complementary to the target mRNA (page 25, lines 25-28). Applicant argues the specification provides the human UBE2K nucleic acid sequence as SEQ ID NO: 2 (page 18, lines 1-2) and since the specification teaches that nucleic acid inhibitors are complementary to a target sequence and provides the target sequence and discloses exemplary lengths for the nucleic acid UBE2K inhibitors, a person of ordinary skill in the art could envision the complete structure of exemplary nucleic acid UBE2K inhibitors for use in the presently claimed methods.
Regarding MPEP 2163 II A3(a)(ii), this is not found persuasive because the specification has not provided sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by the disclosure of relevant, identifying characteristics (i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics). Disclosure of the nucleic acid inhibitors as being single or double stranded, the range in nucleotide length and reciting that they are complementary to a target mRNA and providing the human UBE2K nucleic acid sequence as SEQ ID NO: 2 does not provide a disclosed correlation between structure and function. This does not describe the required structure of the nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K compared to other E2 proteins, and results in treating cancer, reducing proliferation of a cancer cell or inducing cell death of a cancer cell in a human subject in need thereof. The nucleic acid UBE2K inhibitors provided by the instant specification could bind and target different portions of the human UBE2K nucleic acid sequence of SEQ ID NO: 2 and therefore encompasses many possible sequences, and one would not be able to determine the essential structure of the different nucleic acid UBE2K inhibitors that result in preferentially inhibiting UBE2K compared to other E2 proteins, and thereby treating cancer, reducing proliferation of a cancer cell and inducing death in a cancer cell in a subject, which nucleic acid UBE2K inhibitors encompass siRNA, shRNA, antisense oligonucleotides, aptamers, ribozymes and miRNAs as discussed in the written description rejection. In addition, as the claims encompass treating a genus of cancers, the required structure of the UBE2K nucleic acid inhibitor has not been adequately described that is capable of treating any cancer in a subject in need thereof.
Applicant cites MPEP 2163 II A 3(a)(C)(1) on pages 9-10 and that the specification describes a representative number of species of the UBE2K inhibitors recited in the claims as amended and therefore provides adequate written description.
Regarding MPEP 2163 II A 3(a)(C)(1), this is not found persuasive, because the specification does not identify the required structure of any nucleic acid UBE2K inhibitors that is capable of carrying out the recited function to provide a structure-function correlation. As cited in the written description rejection, “For example, disclosure of an antigen fully characterized by its structure, formula, chemical name, physical properties, or deposit in a public depository does not, without more, provide an adequate written description of an antibody claimed by its binding affinity to that antigen, even when preparation of such an antibody is routine and conventional.” See Amgen Inc. v. Sanofi 872 F.3d 1367, 1378, 124 USPQ2d 1354, 1361 (Fed. Cir. 2017) cited in MPEP 2163. Therefore, the disclosure of SEQ ID NO: 2 as the human UBE2K nucleic acid sequence, does not provide adequate written description of a nucleic acid inhibitor of UBE2K that preferentially inhibits UBE2K as compared to other E2 proteins and results in treating cancer.
While the state of the art identifies an siRNA of SEQ ID NO: 1 that inhibits Ubb and reduces UBE2K to treat cancer (Gwangu paragraph 0042), Gwangju does not disclose a UBE2K inhibitor that preferentially inhibits UBE2K as compared to other E2 proteins, and that while Gwangju teaches an siRNA targeted to UBB which reduced UBE2K, it also reduced levels of other E2 proteins and therefore does not preferentially inhibit UBE2K as compared to other E2 proteins. This shows that UBE2K inhibition alone is not sufficient and does not necessarily result in preferential inhibition of UBE2K as compared to other E2 proteins, which further supports the Written Description rejection because the specification and state of the art do not describe the necessary structure of a UBE2K inhibitor that would preferentially inhibit UBE2K as compared to other E2 proteins. Therefore, the examiner is maintaining the 35 U.S.C. 112(a) Written description rejection of claims 1-3,5,12-20 and 34-36.
Scope of Enablement Rejection
Claims 1-3,5,12-19 and 34-36 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating, reducing proliferation of, or inducing cell death in hepatocellular carcinoma or pancreatic cancer cells in a subject by direct administration of an UBE2K antisense oligonucleotide, siRNA, or shRNA complementary to SEQ ID NO: 2 to the site of the tumor, does not reasonably provide enablement for a method of treating, reducing proliferation and inducing death in a genus of cancers in a subject by administering a genus of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2 and that preferentially inhibits UBE2K compared to other E2 proteins, by a genus of administration routes. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
As stated in MPEP §2164.01(a), “there are many factors to consider when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any experimentation is ‘undue’.” These factors include, but are not limited to:
1. The breadth of the claims;
2. The nature of the invention;
3. The state of the prior art;
4. The level of skill in the art;
5. The level of predictability in the art;
6. The amount of direction provided by the inventor;
7. The presence or absence of working examples;
8. The quantity of experimentation necessary needed to make or use the invention based on the disclosure.
The Breadth of the Claims and Nature of the Invention
Claims 1-3,5 and 12-19 encompass administering to a subject a large genera of Ubiquitin Conjugating Enzyme E2 K (UBE2K) nucleic acid inhibitors that are complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2, that preferentially inhibits UBE2K as compared to other E2 proteins that treat cancer, reduce proliferation of a cancer cell in a subject, and induce death of a cancer cell in a subject by any route of administration and claims 1-3,5 and 17-20 encompass treating a large genus of cancers. Claims 13-16 recite the specific solid tumors and leukemia. Claims 34-36 recite nucleic acid inhibitors comprising an antisense nucleic acid molecule, double stranded nucleic acid molecule, wherein the double stranded nucleic acid molecule comprises a double stranded RNA selected from the group consisting of an siRNA, shRNA and a dicer substrate siRNA (DsiRNA), however still encompass treating a large genus of cancers. Claims 17-19 read on the additional agent being a UBE2K inhibitor that is not enabled, or treating a cancer or reducing proliferation and inducing death in a cancer cell that is not enabled.
The State of the Prior Art
Before the effective filing date, the state of the art is limited regarding treating a genus of cancers with a genus of UBE2K nucleic acid inhibitors, and is silent regarding treating cancer with a UBE2K inhibitor that preferentially inhibits UBE2K as compared to other E2 proteins. KR 20150016816, hereinafter “Gwangju” (Published 3 June 2015), and cited on an IDS, teaches PC3 cells transfected with UbbsiRNA were subcutaneously administered to mouse xenograft models and that the growth of PC3 cell-derived tumors was inhibited by UBB knockdown, resulting in about 40% reduction in tumor volume and weight [0080]. Gwangju teaches the amount of Ub-binding enzyme, e.g., Ube2K/E2-25K to Ub was reduced by Ubb siRNA treatment [0069], and proliferation of PC3 and HepG2 hepatocellular carcinoma cells was inhibited using siRNA [0071-0072]. However, Gwangju does not teach that the UbbsiRNA preferentially inhibits UBE2K as compared to other E2 proteins.
Regarding nucleic acid based cancer therapeutics, MacLeod et al. (The Journal of Clinical Pharmacology 2017, 57(S10) S43-S59), teach that siRNA based therapeutics have great potential as cancer therapeutics, however many challenges remain, including rapid degradation, poor cellular uptake and off-target effects, but improvements in chemical modifications and nanocarriers have potential to make the translational process faster and more effective (page S52, right column). Regarding antisense oligonucleotides, MacLeod et al. teach Generation 2.0 ASOs have show less potent effects in extrahepatic and extrarenal tissues that accumulate lower concentrations of these drugs, including skeletal muscle and tumors, and therefore the clinical experience with this generation of ASOs in cancer treatment has been and is still limited (page S53, right column). Macleod et al. teach Generation 2.5 ASOs which incorporates a constrained ethyl nucleoside modification significantly increases affinity for the target RNA and has increased potency in vitro and in vivo compared to Generation 2.0 ASOs, and increases the range of tissue in which potent antisense pharmacology can be achieved to include difficult to target tissues such as tumors and skeletal muscle (Page S54, left column). MacLeod et al. teach some key challenges remail with RNA therapeutics, including the ADME properties of either unformulated ASOs and miRNA therapeutics or nanoparticle encapsulated siRNAs are limited, and upon systemic delivery, these agents distribute broadly to most tissues, although the liver and kidney are the main target organism and tumors accumulate less. Uptake into tumor cells themselves and release of drug from endosomal compartments into the respective productive compartments (the nuclease for ASOs and miRNAs and the cytoplasm for siRNAs) also limit the maximal activity of these agents (Page S55, left column). MacLeod et al. teach the future of RNA therapeutics for cancer and that ideally can be selectively delivered to the tumor cells of interest with a targeted delivery moiety (Page S55, left column).
Regarding the route of administration, Dai et al. (J. Mater. Chem. B, 2016, 4, 6758-6772) teach that pharmaceutical preparations for tumor therapy are usually administered orally or by injection, however the drug will be either translocated systemically or rapidly removed from the body which leads to lower bioavailability of drugs and higher toxic side effects of the medication (pages 6759-6760). Dai et al. teach one strategy to address this is functionalization of targeting moieties to deliver the drug to the target site (page 6760). Dai et al. teach passive and active targeting drug delivery systems to overcome the disadvantages discussed above (page 6762-6764). Dai et al. teach that active targeting is achieved by attaching specific ligands/antibodies to the nanocarriers which recognize receptors or antigens on the tumor cell surfaces and improve uptake and enhance therapeutic efficacy of anticancer agents and reduce undesired side effects (page 6763, Section 3.2.1). Dai et al. teach there are several drug delivery systems that are in clinical trials using passive targeting to deliver therapeutics such as siRNA, CPT, PTX and SN38 to tumor sites with good antitumor activity (page 6767, Table 2) and preclinical studies using actively targeting drug delivery systems (page 6768, Table 3).
Therefore, the state of the art teaches siRNA that reduces UBE2K and proliferation of hepatocellular carcinoma cells, and that there are disadvantages to oral and intravenous injection of anti-cancer drugs for treating cancer that may affect the efficacy of treatment and that siRNA based therapeutics have great potential as cancer therapeutics but challenges include rapid degradation, poor cellular uptake and off-target effects and the need for chemical modification or an effective delivery system in order to reach or be taken up by the tumor. There is a lack of teaching in the state of the art for UBE2K inhibitors that preferentially inhibit UBE2K as compared to other E2 proteins and result in treating a genus of cancers, reducing proliferation of a cancer cell or induce death of a cancer cell in a subject.
The Level of Predictability in the Art
The instant claimed invention is highly unpredictable due to the claims encompassing treating any cancer, reducing proliferation and inducing death of any type of cancer cell in a subject by administering a large genera of nucleic acid UBE2K inhibitors that are complementary to a human UBE2K mRNA transcript encoded by the nucleic acid sequence of SEQ ID NO: 2 by any administration route. The large number of species encompassed by the genus of UBE2K nucleic acid inhibitors complementary to a human UBE2K mRNA transcript encoded by the nucleic acid sequence of SEQ ID NO: 2 and administration to the subject by any route, adds to the unpredictability of the claimed invention. The genus of UBE2K nucleic acid inhibitors that preferentially inhibit UBE2K as compared to other E2 proteins encompasses siRNA, antisense oligonucleotides, ribozymes, miRNAs, sgRNA, aptamers, shRNA that are complementary to SEQ ID NO: 2, which all have different structures and mechanisms of action, and therefore one skilled in the art cannot use the information provided by the specification regarding siRNA and shRNA UBE2K inhibitors and apply to the other species of the genus. Neither the specification, nor the prior art disclose any specific miRNAs, aptamers or ribozymes that are considered preferential UBE2K inhibitors and that treat a genus of cancers, reduce proliferation or induce death of cancer cells in a subject. In addition, as stated above in the State of the Prior art section, there is a lack of teaching in the state of the art for nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins and result in treating a genus of cancers, reducing proliferation of a cancer cell or induce death of a cancer cell in a subject.
It is also noted that the instant claims do not recite that the nucleic acid inhibitor has any chemical modifications or is part of a delivery system such as a nanoparticle or includes a targeting system to reach the cancer cells. This adds to the unpredictability that a nucleic acid inhibitor would be capable of reaching target cancer cells before being degraded and carry out the recited effect of treating cancer, reducing proliferation of cancer cells or inducing death of cancer cells.
It would be unpredictable that the nucleic acid UBE2K inhibitor can be administered to the subject by any route of administration, other than direct administration to the site of the tumor, to treat a large genus of cancers. For example, it would be unpredictable that oral administration of a nucleic acid inhibitor would result in treatment of liver cancer, due to the drug being removed from the body, and would result in lower bioavailability.
If one skilled in the art cannot readily anticipate the effect of a change within the subject matter to which that claimed invention pertains (e.g., a method of treating cancer, a method of reducing proliferation of a cancer cell, a method of inducing death of a cancer cell in a subject in need thereof, the method comprising administering to the subject a nucleic acid inhibitor complementary to SEQ ID NO: 2 that preferentially inhibits UBE2K as compared to other E2 proteins), then there is a lack of predictability in the art. The court has indicated that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. (See In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970)). This is because it is not obvious from the disclosure of one species, what other species will work.
The Amount of Direction Provided by the Inventor and
The Presence or Absence of Working Examples
Regarding claims 1-3,5,12-19 and 34-36, the specification does not enable any
person skilled in the art to which it pertains to make and/or use the invention
commensurate in scope with the claims. Claim 20 is not rejected as the recited
chemotherapeutic agents are well known agents that are known in the art to be
successful in treating various cancers.
The specification contemplates UBE2K nucleic acid inhibitors (e.g. antisense, siRNA, shRNA, dsiRNA, etc.) and contemplates a large genera of administration routes, including orally, parenterally, topically, inhalation, intravenous, intramuscular, subcutaneous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections or injection directly into the tumor (pages 5-6). The specification contemplates that the UBE2K inhibitor can act by any mechanism, by inhibiting the expression at the RNA or protein level or inhibiting the activity of UBE2K, and in some embodiments is a specific inhibitor of UBE2K and does not substantially reduce the expression or activity of other polypeptides other than UBE2K (page 19).
The examples disclose that UBE2K was transiently knocked down using siRNA in Miapaca2, HepG2, SKHEP1, Hep3B, MDAMB231, SKBR3, T47D and BT549 cells (Example 2, page 63), and that UBE2K siRNA mediated knockdown resulted in a 50% decrease in cell number in Miapaca2 pancreatic cancer cells, 30% decrease in cell number in SKHEP1 and HepG2 hepatocellular carcinoma cells, and no effect of the siRNA in the remaining 5 cancer cell lines (page 63; Table 4 page 64). Example 5, pages 68-69 disclose UBE2K knock-down with shRNA. Figure 16 shows confirmation of UBE2K knockdown in UBE2K shRNA transduced MiaPaca2 cell lines. No sequences of the siRNAs or shRNA for UBE2K knock-down are disclosed.
Therefore, as the examples disclose that UBE2K siRNA knockdown only resulted in a decreased cell number in pancreatic cancer cells and hepatocellular carcinoma cells, and no effect in the other 5 cancer cell lines and the state of the art teaches Ube2K/E2-25K to Ub was reduced by Ubb siRNA treatment and proliferation of HepG2 hepatocellular carcinoma cells was inhibited (Gwangju, paragraphs 0069,0071,0072), the instant claims are only enabled for treatment, reducing proliferation of, and inducing cell death of pancreatic cancer and hepatocellular carcinoma cells in a subject by direct administration. The specification and state of the art do not provide enablement for treating, reducing proliferation of, or inducing cell death of other types of cancer cells other than pancreatic cancer and hepatocellular carcinoma or by non-direct routes of administration to the site of the tumor of a genus of UBE2K nucleic acid inhibitors.
The Quantity of Experimentation Necessary
Regarding claims 1-3,5,12-19 and 34-36, in light of the unpredictability surrounding the breadth of the claimed method of treating cancer, a method of reducing proliferation of a cancer cell, a method of inducing death of a cancer cell in a subject in need thereof, the method comprising administering to the subject a UBEK2 nucleic acid inhibitor complementary to a human UBE2K mRNA transcript encoded by SEQ ID NO: 2, wherein the UBE2K inhibitor preferentially inhibits UBE2K as compared to other E2 proteins, one wishing to practice the presently claimed invention would be unable to do so without engaging in undue experimentation. One of ordinary skill in the art would not be able to use the information provided by the instant specification to carry out the full scope of the invention as claimed, as there is no instruction as to how to make or use other UBE2K nucleic acid inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins to carry out the claimed invention and result in treating a genus of cancers. In absence of such information in the specification as well as the state of the art, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation to practice the full scope of the claimed method.
Conclusion of 35 U.S.C. 112(a) (Enablement) Analysis
After applying the Wands factors and analysis to claims 1-3,5,12-19 and 34-36, in view of the applicant’s entire disclosure, it is concluded that the specification is not enabled for the full scope as discussed above.
Response to Arguments
Applicant's arguments filed 09/19/2025, have been fully considered but they are not persuasive.
Applicant cites In Re Marzocchii and Horton, 169 U.S.P.Q. 367 on page 10, which states “It is the Patent Office’s burden to present evidence that there is some reason to dispute the enablement provided in the specification”. Applicant argues that the test of enablement is whether one reasonably skilled in the art could make or use the invention from the disclosures in the patent coupled with information known in the art without undue experimentation per MPEP 2164.01.
This is not found persuasive because the Examiner has evaluated and discussed each of the Wands factors as described in the Scope of Enablement rejection to determine whether there is sufficient evidence to determine if the disclosure does not satisfy the enablement requirement and whether experimentation is undue. The examiner has brought up numerous reasons for each of the Wands factors, that support the scope of enablement rejection. This includes the breadth of the claims which encompasses a genus of nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins, and the genus of cancers being treated and genus of administration routes and lack of chemical modification of the nucleic acid inhibitor or an effective delivery system to reach the target cancer tissues/cells; the lack of teaching in the state of the art regarding UBE2K inhibitors that preferentially inhibits UBE2K compared to other E2 proteins and that result in the function of treating a genus of cancers, reducing proliferation of and inducing death of a cancer cell in a subject; the high unpredictability in the art with the lack of teaching of nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K compared to other E2 proteins, genus of cancers being treated and genus of administration routes; the lack of guidance provided by the specification and absence of working examples regarding the genus of nucleic acid UBE2K inhibitors that preferentially inhibits UBE2K compared to other E2 proteins that can treat a genus of cancers by a genus of administration routes, which in turn supports the case for undue experimentation. Therefore, the examiner has determined based on evaluating each of the Wands factors, that in the absence of such information in the specification as well as the state of the art, a person of ordinary skill in the art would reasonably require an undue quantity of experimentation to practice the full scope of the claimed method.
Applicant argues on page 11 that the specification provides methods for identifying nucleic acid UBE2K inhibitors that preferentially inhibit UBE2K as compared to other E2 proteins, and the specification provides methods of producing nucleic acid inhibitors on page 23, lines 1-4, and the claims as amended require that the nucleic acid inhibitor is complementary to a human UBE2K mRNA transcript encoded by the nucleic acid of SEQ ID NO: 2, and a person of ordinary skill in the art could prepare nucleic acid inhibitors that are complementary to SEQ ID NO: 2 using only routine experimentation. Applicant cites page 19, lines 25 through page 20 line 8 of the specification for methods for identifying nucleic acid inhibitors of UBE2K and that the person of ordinary skill in the art could prepare and identify a nucleic acid UBE2K inhibitor that preferentially inhibits UBE2K as compared to other E2 proteins based on the teachings in the specification.
This is not found persuasive because while the specification provides methods known in the art for identifying UBE2K inhibitors on page 19, one of ordinary skill in the art would not be able to use the information provided by the instant specification to carry out the full scope of the invention as claimed. There is no instruction as to how to make or use a genus of nucleic UBE2K inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins and that results in treating, reducing proliferation of, and inducing cell death in a genus of cancers, to carry out the claimed invention.
Applicant argues on page 12 that the specification provides working examples demonstrating use of nucleic acid UBE2K inhibitors for treatment of cancer, including Examples 2-4 that demonstrate the use of an siRNA UBE2K inhibitor for inhibiting growth of different cancer cell lines and demonstrate UBE2K inhibition was effective in reducing proliferation of pancreatic cancer and hepatocellular carcinoma cell lines, and Example 5 demonstrates using shRNA UBE2K inhibitor for reducing growth of pancreatic cancer cells, and therefore based on the teachings in the specification, a person of ordinary skill in the art could identify UBE2K inhibitors and use them in the treatment of cancer without undue experimentation.
This is not found persuasive, because as described in the scope of enablement rejection, the examples disclose that UBE2K siRNA knockdown only resulted in a decreased cell number in pancreatic cancer cells and hepatocellular carcinoma cells, and no effect in the other 5 cancer cell lines and the state of the art teaches Ube2K/E2-25K to Ub was reduced by Ubb siRNA treatment and proliferation of HepG2 hepatocellular carcinoma cells was inhibited (Gwangju, paragraphs 0069,0071,0072). Therefore, the instant claims are only enabled for treatment, reducing proliferation of, and inducing cell death of pancreatic cancer and hepatocellular carcinoma cells in a subject by direct administration of a UBE2K antisense oligonucleotide, siRNA, or shRNA complementary to SEQ ID NO: 2. The specification and state of the art do not provide enablement for treating, reducing proliferation of, or inducing cell death of other types of cancer cells other than pancreatic cancer and hepatocellular carcinoma or by other means of administration other than direct administration to the site of the tumor by administering a genus of UBE2K inhibitors that preferentially inhibits UBE2K as compared to other E2 proteins. Therefore, the examiner concludes and maintains that the specification is not enabled for the full scope as claimed.
Conclusion
Claims 1-3,5,12-20 and 34-36 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to STEPHANIE L SULLIVAN whose telephone number is (703)756-4671. The examiner can normally be reached Monday-Friday, 7:30-3:30 EST.
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/STEPHANIE L SULLIVAN/Examiner, Art Unit 1635
/ABIGAIL VANHORN/Primary Examiner, Art Unit 1636