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 .
This action is in response to the amendment filed 01/21/2026, in which claim 12 was amended and claim 14 was previously presented. Claims 12 and 14 are currently pending.
Applicant’s arguments have been thoroughly reviewed, but are not persuasive for the
reasons that follow. Any rejection and objections not reiterated in this action have been
withdrawn. This action is FINAL.
Claim Rejections - 35 USC § 112(a)
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.
This rejection was made in the Office action mailed 10/21/2025 and has been rewritten to address the amendment to the claims in the reply filed 01/21/2026.
Claims 12 and 14 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 enablement requirement. The claim(s) contains
subject matter which was not described in the specification in such a way as to enable one skilled
in the art to which it pertains, or with which it is most nearly connected, to make and/or use the
invention. All citations cited in the prior office action filed 10/21/2025.
Enablement is considered in view of the Wands factors (MPEP 2164.01(A)). These
include: nature of the invention, breadth of the claims, guidance of the specification, the
existence of working examples, state of the art, predictability of the art and the amount of
experimentation necessary. All of the Wands factors have been considered with regard to the
instant claims, with the most relevant factors discussed below.
Nature of the invention:
The claims are drawn to a method of treating a tumor disease. The specification defines “tumor” to mean “cells which exhibit relatively autonomous growth, so that they exhibit an aberrant growth phenotype characterized by a significant loss of control of cell proliferation.” See page 10, lines 1-6. Examples of tumors include precancerous, benign, malignant, metastatic and non-metastatic cells (e.g., page 10, lines 4-6). The claims are drawn to the step of “administering an effective amount of Myb-related transcription factor (MYPOP) L form to tumor cells of a patient for the treatment of a tumor disease wherein the tumor disease to be selected from the group consisting of melanoma, breast cancer, lung cancer, liver cancer, gastric cancer, colon cancer, cervical carcinoma, pancreatic cancer, prostate cancer, ovarian cancer, lymphoma, leukemia, kidney cancer, bladder cancer, or endometrial cancer”. Claim 14 limits the tumor disease to an oncogenic human papillomavirus (HPV)-induced cancer. The nature of the invention is complex in that one must be able to administer MYPOP L form to tumor cells of a patient in an amount sufficient to treat or prevent any tumor disease or cancer.
Breadth of the claims:
The claims broadly claim the expression of MYPOP L form protein in the tumor cells is achieved by delivering a vector comprising MYPOP L form encoding nucleic acid molecule to the tumor cells.
Guidance of the specification and existence of working examples:
At page 1, lines 16-23, the specification states the following:
It was found previously by the inventors that MYPOP acts a restriction factor for the oncogenic human papilloma virus (HPV) types 16 and 18 because it represses the long control region (LCR) activity of both viruses (Wüstenhagen et al., The Myb-related protein MYPOP is a novel intrinsic host restriction factor of oncogenic human papillomaviruses, Oncogene, 17 July 2018). It was further found by the inventors that MYPOP is eliminated in HPV-transformed tumor cells on a posttranscriptional level. As such, total MYPOP amounts were found to be strongly reduced in virus HPV-transformed cell lines in cervical cancer.
The specification goes on to state the following at page 1, lines 25-29:
Now, the inventors found that MYPOP is also strongly down-regulated in all other tested tumor cells like melanoma, breast, hepatoma and lung cancers. This was verified in tumor samples from lung cancer patients. In these primary lung tumor cells and in other tumor cell lines, MYPOP restoration led to a block of cell proliferation. Therefore, MYPOP is a general tumor suppressor that is absent in all tumor cells and recovery of MYPOP heals cancer.
See also the paragraph bridging pages 2-3.
The specification teaches that MYPOP exists in two isoforms, specifically one with a
molecular weight of 60 kDa and another with a molecular weight of 42 kDa (e.g., page 3, lines 8-
10). The specification defines the term “L form” to refer to “the 60 kDa isoform of MYPOP”
(page 7, lines 25-27). The specification teaches that it is specifically the L form of MYPOP that
is reduced or absent in tumor cells (e.g., page 3, lines 8-14; Example 1; Figs. 1-4). The specification teaches that restoration of the protein levels of the L form of MYPOP result in cell death or blockage of tumor cell divisions in cultured cells (e.g., page 18, lines 12-27; Example 3; Figs. 7-9). Example 3 of the specification is based upon the transfection of cultured cells with a MYPOP expression plasmid (e.g., paragraph bridging pages 24-25). The specification teaches that MYPOP-N comprising the DNA binding domain to modulate promoter activity reduces cell proliferation of cancer cells in culture (e.g., Example 4; Fig. 11). Example 4 does not disclose the type of vector (e.g., retroviral or plasmid) that contains the FLAG tag and the MYPOP coding sequence.
The specification envisions the restoration of MYPOP expression in tumor cells by gene therapy (e.g., page 16, lines 23-25; page 18, lines 35-37). The specification envisions the administration of MYPOP-expression viral or non-viral vehicle, plasmid or vector to the patient (e.g., page 16, lines 30-36). The specification indicates that the term “vector” refers to any molecule used to transfer coding information to a host cell and includes vectors such as plasmid or virus (e.g., page 10, lines 30-37). The specification envisions the use of a retroviral vector as the genetic construct to deliver a MYPOP gene (e.g., page 20, lines 6-14). The specification envisions expressing the N-terminus containing “active domains to inhibit the progression of cancer and sensitize the tumor cells to therapeutic drugs or gene therapy” (page 18, lines 23-26). The specification envisions the prevention of tumor diseases by treating a subject with normal levels of MYPOP (e.g., page 16, lines 26-36). The specification envisions the administration of MYPOP protein (e.g., page 4, lines 19-20 and 26-27; page 17, lines 29-31; page 19, lines 14-16). The specification envisions administration of an N-terminus of MYPOP, preferably an N-terminus of MYPOP that comprises the amino acid sequence of SEQ ID NO: 2 (e.g., page 15, lines 4-17). The specification envisions the administration of recombinant cells that produce a complete, intact delivery vector, the cells can be administered as a pharmaceutical preparation (e.g., page 20, lines 6-14). The specification provides general guidance for the administration of therapeutic agents (e.g., page 17, lines 29-37; page 18, line 35 to page 19, line 2; page 19, line 16 to page 22, line 34). The drawings do not show the structure of any vectors encoding MYPOP or any MYPOP proteins to be administered. The specification does not contain any working examples of the claimed method. No vector encoding MYPOP and no MYPOP protein is administered to tumor cells in a patient such that the administration results in treating or preventing a tumor disease.
Predictability and state of the art:
The state of the art with regard to the functions of MYPOP were underdeveloped. The Myb-related transcription factor (MYPOP, a.k.a., p42POP) was first identified in mice by Lederer et al (Profilin regulates the activity of p42POP, a novel Myb-related transcription factor. Journal of Cell Science, Vol. 118, No. 2, pages 331-341, 2005) cited in a prior office action. Lederer et al (2005) teaches that MYPOP is widely expressed in mouse tissue and binds to profilin protein (e.g., paragraph bridging pages 331-332). Lederer teaches that MYPOP contains a single Myb-like domain, an acidic domain, nuclear import and export signals, a leucine zipper and a proline cluster mediating profiling binding, where MYPOP protein functions to repress transcription, and where repression activity is altered by interaction with profiling (e.g., paragraph bridging pages 331-332; Fig. 1). The Myb-domain is located at the N-terminus of the MYPOP protein (e.g., Lederer et al. 2005 at Fig. 1).
Later art related to the function of human MYPOP is published as Wüstenhagen et al. (Oncogene, Vol. 37, pages 6275-6284, July 17, 2018, including pages 1/6-6/6 of Supplementary Information, and pages 1/10-10/10 of Supplementary Methods). Wüstenhagen et al teaches that MYPOP acts to repress transcription of genes of the oncogenic human papilloma virus (HPV) subtypes 16 and 18 (e.g., page 6277, right column). Further, Wüstenhagen et al teaches that overexpression of MYPOP resulted in a decrease in the number of HPV16- or HPV18-immortalized and nonvirally transformed keratinocytes, indicating the MYPOP is able to block proliferation of tumor cells (e.g., page 6277, right column). Until the publication of the Wüstenhagen reference, the function of MYPOP in tumor diseases or oncogenic HPV infections was not known. It is noted that the specification attempts to attribute the Wüstenhagen reference to the inventor (e.g., page 1, lines 16-23); however, the specification does not provide a rule 77(b)(6) statement that provides a reasonable explanation of the presence of additional authors on the prior art reference in that no explanation is provided. Other than a potentially inventor-originated disclosure, the prior art does not teach the relationship of MYPOP, or fragments thereof, to tumor disease or HPV infection.
Because the art related to MYPOP as a tumor suppressor in the context of treating tumor disease in a patient was not well developed, the area is considered to be unpredictable based on the teachings in the field of therapy with tumor suppressors. Altinoglu et al (Biomaterials Science, Vol. 4, pages 1773-1780, 2016) teaches that while the involvement of the tumor suppressor phosphatase and tensin homolog deleted on chromosome 10 (PTEN) was understood in terms of its ability to inhibit angiogenesis, cell proliferation and migration, and to induce cellular apoptosis, its therapeutic potential in medicine was in its infancy (e.g., page 1779, right column). Altinoglu et al states, “gene therapy as a therapeutic platform itself has numerous challenges to face before acceptance as a widespread treatment approach, such as initiating unsolicited immune response, the disruption of normal genes upon insertion into the genome,
and nonspecifically and permanently affecting off-target cells.” See page 1773, right column,
full paragraph. With regard to protein delivery, Altinoglu et al teach, “despite extensive research
of protein pharmaceuticals, intracellular delivery remains a challenge for modern medicine with
difficulties in loading, release upon entry into the cells, and complicated delivery vehicle
fabrication.”
Tazawa et al (Recent Results in Cancer Research, Vol. 209, pages 1-15, 2016) teaches the unpredictability of using any method of administering a tumor suppressor into a patient for the treatment of a tumor. For example, Tazawa et al teach that liposome-mediated delivery of DNA encoding p53 has too low of a transfection efficiency to induce cell death in in vivo tumor tissues (e.g., page 5, section 3.1). Tazawa et al teach that further improvement of liposome-based delivery systems is needed to efficiently induce p53-mediated cell death within tumor tissues (e.g., page 5, section 3.1). In contrast, Tazawa et al teach that replication-deficient adenoviral delivery of exogenous p53 has been shown to efficiently induce expression of exogenous p53 gene and exert a subsequent antitumor effect in preclinical in vitro and in vivo experiments (e.g., page 5, section 3.2, 1st paragraph). Tazawa et al teach that the adenovirus can induce ectopic expression of exogenous p53 in various types of human cancers more strongly than that induced by a plasmid-based delivery system (e.g., page 9, section 3.4, 1st paragraph). However, Tazawa et al teach that the adenovirus can only enter cells expressing coxsackie and adenovirus receptors (CAR), and CAR-negative tumors will escape from being eradicated by adenovirus-based p53 replacement therapy (e.g., page 9, section 3.4, 1st paragraph).
Chira et al (Oncotarget, Vol. 6, No. 31, pages 30675-30703, September 2015) teaches that delivering a genetic therapeutic product to a specific group of target cells without local or systemic adverse events is complex and requires research to overcome the limitations imposed by gene therapy vectors (e.g., page 30691, left column, last paragraph). Accordingly, one would have recognized that it would have been unpredictable to translate the disclosed in vitro studies showing MYPOP L form functions as a tumor suppressor to in vivo delivery of MYPOP expressing nucleic acid or cells, or MYPOP protein for the treatment or prevention of any tumor disease.
Amount of experimentation necessary:
The quantity of experimentation necessary to carry out the claimed invention is high, as the skilled artisan could not rely on the prior art or the present specification to teach how to make and use the claimed methods. With any nucleic acid, one would have to determine how to deliver the given nucleic acid or protein to the appropriate target cells with specificity and efficiency, and how to get sufficient expression to induce at least some therapeutic effect. Since neither the prior art nor the specification provides the answers to all of these questions, it would require a large quantity of trial-and-error experimentation by the skilled artisan to do so. Success with one MYPOP L form sequence and delivery vector for one type of tumor disease would not confer an expectation of success with a different combination of sequence, delivery vector or method, or tumor disease.
In view of the breadth of the claims and the lack of guidance provided by the specification as well as the unpredictability of the art, the skilled artisan would have required an undue amount of experimentation to make and/or use the claimed invention. Therefore, claims 12 and 14 are not considered to be enabled by the instant specification.
Response to Arguments - Claim Rejections - 35 USC § 112(a)
Applicant's arguments filed 10/07/2025 have been fully considered but they are not persuasive.
Applicant traverses’ the rejection of claims 12 and 14 under 35 U.S.C. 112 (a). Applicant states the specification teaches MYPOP for use in tumor therapy and the specification demonstrates for various types of cancer that restoration of the MYPOP L form in cancer cells reduces cell proliferation and induces cell death. Applicant states “For example, the specification teaches that restoration of MYPOP reduces cell proliferation and induces cell death in cancer cells such as breast cancer cells (see, e.g., Example 3, paragraph [0145], and Figure 8), lung cancer cells (see, e.g., Example 3, paragraph [0146], and Figure 9), liver cancer cells (see, e.g., Example 5, paragraph [0156], and Figure 15), lung squamous cancer cells (see, e.g., Example 5, paragraph [0156], and Figure 15), and adenocarcinoma cells (see, e.g., Example 5, paragraph [0156], and Figure 15)”.
Applicant states the specification also teaches that MYPOP-vector gene therapy is functional in reducing cell proliferation of keratinocyte cancer cell lines (see, e.g., Example 5, paragraph [0159], and Figure 17) and lung cancer cell lines (see, e.g., Example 5, paragraph [0160], and Figure 18) with no significant cytotoxic effect on normal, non-tumor cells (see, e.g., Example 5, paragraph [0161], and Figure 19).
These arguments are not found persuasive due to the art teaching the unpredictability of translating cell-based studies to patient administration. It is unpredictable that the delivery of nucleic acids encoding the MYPOP L form would provide high enough transfection for induction of tumor cell death. Specifically, Tazawa teaches that liposome-mediated delivery of DNA encoding p53 has too low of a transfection efficiency to induce cell death in in vivo tumor tissues (e.g., page 5, section 3.1) and in contrast the adenovirus can induce ectopic expression of exogenous p53 in various types of human cancers more strongly than that induced by a plasmid-based delivery system (e.g., page 9, section 3.4, 1st paragraph); However, the adenovirus can only enter cells expressing coxsackie and adenovirus receptors (CAR), and CAR-negative tumors will escape from being eradicated by adenovirus-based p53 replacement therapy (e.g., page 9, section 3.4, 1st paragraph). Furthermore, the cited prior art demonstrates the unpredictability of translating cell-based studies to therapeutic methods involving the expression of a tumor suppressor protein. The arguments regarding the dependent claims are not found persuasive due to the dependent claims being broader and failing to narrow the scope of the independent claim by not specifically requiring the L-form of the MYPOP protein.
Applicant provides data within the remarks (Pages 5-7) regarding MYPOP-AAV gene therapy in high-grade serous ovarian cancer patients. However, this data cannot be evaluated fully due to the remarks not containing a citation of the data, a factual affidavit and/or declaration from the Applicant’s themselves. “Applicant may submit factual affidavits under 37 CFR 1.132 or cite references to show what one skilled in the art knew at the time of filing the application” (See MPEP §2164.05).
Conclusion
THIS ACTION IS MADE FINAL. 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 mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ALEXANDRA ROSE LIPPOLIS whose telephone number is (703)756-5450. The examiner can normally be reached Monday-Friday, 8:00am to 5:00pm EST.
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/ALEXANDRA ROSE LIPPOLIS/Examiner, Art Unit 1637
/CELINE X QIAN/Primary Examiner, Art Unit 1637