DETAILED ACTION
Notice of Pre-AIA or AIA Status
1. 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
2. Claims 1-4, 6-9, 45, 49-52, 55 and 56 are pending.
Claims 5, 10, 46, 57 and 58 have been cancelled.
Claims 1 and 2 have been amended.
Claims 1-4, 6-9, 45, 49-52, 55 and 56 with species (Polq inhibitor): an antisense compound is examined on the merits.
Withdrawn Grounds of Rejection
Claim Rejections - 35 USC § 103
3. The rejection of claim(s) 1-4, 6-9, 45, 49-52, 55 and 56 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sherman et al., US 2010/0003192 A1 (published January 7, 2010), and further in view of Mateos-Gomez et al., (Nature 518(7538): 254-257 with Supplemental Information pages 1-12, published online February 2, 2015) is withdrawn. Claim 5 has been cancelled.
While the Patent Trial and Appeal Board (PTAB) affirmed the instant 103 rejection, it has been withdrawn in lieu of the Board setting forth a new 103 rejection, herein, see Decision Summary mailed March 3, 2026, page 11; and entire document.
4. The rejection of claim(s) 10, 46, 57 and 58 under 35 U.S.C. 103 as being unpatentable over Sherman et al., US 2010/0003192 A1 (published January 7, 2010), and further in view of Mateos-Gomez et al., (Nature 518 (7538): 254-257 with Supplemental Information pages 1-12, published online February 2, 2015) is withdrawn in light of the cancellation of the claims, see Listing of Claims submitted May 4, 2026.
New Grounds of Rejection
Claim Rejections - 35 USC § 103
5. The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
6. The rejection of claim(s) 1-4, 6-9, 45, 49-52, 55 and 56 under 35 U.S.C. 103 as being unpatentable over Sherman et al., US 2010/0003192 A1 (published January 7, 2010), and further in view of Mateos-Gomez et al., (Nature 518(7538): 254-257 with Supplemental Information pages 1-12, published online February 2, 2015) as evidenced by Rodon et al., The Oncologist 15: 37-50 (2010), Spain et al., Expert Opinion Pharmacotherapy 17(7): 1031-1038 (published online 8 April 2016) and Gross et al. J Clinical Investigation 125(5): 1780-1789 (May 2015) is maintained.
Applicant presents data in Figure 4E and Figure 4F, wherein treatment of ovarian HR-deficient tumors with PARPi and shPOLQ resulted in a synergistic effect as the combination increased the therapeutic agents’ effectiveness as evidenced by the tumor volume reduction, see Remarks submitted May 4, 2026, pages 6-8; and said Figures on pages 6 and 8.
Applicant further argues the said combination of prior art references with the evidentiary references do not make obvious the claimed invention, wherein administering a PARPi with a POLQ “…inhibitor would result in a greater than additive reduction in tumor volume or extension of survival as compared to treatment with either…” agent alone, see page 9 of the Remarks, last paragraph (para).
Applicant concludes arguments stating the “…synergistic effect would not have been expected by a person having ordinary skill in the art over Sherman in view of Mateos Gomez”, see page 9, 2nd para. “Nothing in Sherman in view of Mateos-Gomez indicates that treating an HR deficient cancer with a PARP inhibitor and a PolΘ inhibitor would result in a greater than additive reduction in tumor volume or extension of survival as compared to treatment with either a PolΘ inhibitor or a PARP inhibitor alone. Further, nothing in Rondon, Spain, or Gross cures the deficiencies of Sherman in view of Mateos-Gomez as described herein.”, see page 9, last para. These arguments have been carefully considered, but fail to persuade.
Applicant’s arguments are not commensurate in scope as the evidence presented herein reads on a sole HR-deficient tumor, ovarian cancer, xenografted A2780-shFANCD2 tumors, while independent claim 1 reads broadly on any HR-deficient cancer, as well as dependent claims except claims 55 and 56. Claim 56 recites breast cancer.
At the time of filing, the instant application it was art known that PARP1 facilitates the recruitment of Pol θ to DSB repair and they both are part of the same signaling pathway, see Mateos-Gomez, bridging paragraph of pages 256 and 257. Pol θ is recruited by PARP1 to promote alternative non-homologous end joining (alt-NHEJ) at the expense of homology-directed repair (HDR), hence these two enzymes are necessary for damaging or inhibiting DNA repair and deemed targets for therapeutic intervention, see Figure 3 of Mateos-Gomez; and entire reference.
Moreover, the evidentiary references recognize the need to treat cancers using drugs that target different members of the same pathway as show in Rodon and Spain and further substantiated in Gross, see Board decision, pages 8-10.
To arrive at a proper determination under 35 U.S.C. 103, the Examiner must undertake the role of the person of ordinary skill in the art utilizing factual information and arriving at a legal conclusion based on the facts, devoid impermissible hindsight and rationale for making a proper case of prima facie of obviousness. The Examiner has provided articulated reasoning with rational underpinning to support the legal conclusion of obviousness. In summary, there must be some suggestion or motivation; a reasonable expectation of success; and the prior art references must teach or suggest all the claim limitations.
The combination of references and evidentiary references would not change the principle of operation of the prior art invention being modified, hence the teachings of the references are sufficient to render the claims prima facie obvious. Accordingly, the rejection is maintained.
Sherman teaches treating human breast cancer deficient in homologous recombination (HR) repair with a poly (ADP-ribose) polymerase (PARP) inhibitor in combination with anti-tumor agents including chemotherapy, mitomycin C and antisense oligonucleotides, see page 2, section 0011; page 11, section 0061; page 13, section 0081; page 17, section 0119; page 25, section 0164; and page 26, last sentence in section 0178. The combination therapy can be administered in separate dosages, simultaneously and sequentially, see page 23, section 0141.
Additionally, Sherman teaches breast cancer, as well as ovarian cancer have increased PARP activity and upregulated in these cancers comparatively to others, see page 32, section 0232; and Figure 1. Likewise, “[w]omen who have BRCA mutations have been shown to have between a 36% and 85% chance of developing breast cancer and a 16% and 60% chance of developing ovarian cancer.”, see page 38, section 0335.
As evidenced by Rodon and Spain, there is “…the need to treat cancers using drugs that target different members of the same pathway”, as well as combination therapy against distinct targets within the same pathway is beneficial, see PTAB decision, last paragraph (para.) on page 8; Rodon, page 41, column (col.) 1, lines 6-14; page 1031, 2nd col., lines 9-12 and corresponding Figure 1 of Spain on page 1032 at close of instant rejection; and Gross page 1784, col. 1, sentences before Drug…segment.
Sherman does not teach explicitly teach the combination therapy includes polymerase theta (also known as Polq, POLQ or Polθ) inhibitor, a Polθ antisense compound with a PARP inhibitor, wherein the combination of the two agents are synergistic in reducing tumor volume and/or extending survival as compared to the POLQ inhibitor alone or the PARPi alone.
Sherman teaches “tumors that are homologous recombination deficient are identified by evaluating levels of PARP expression”, see page 27, section 0180. “PARP up-regulation may be an indicator of defective DNA-repair pathways and unrecognized BRCA-like genetic defects. Assessment of PARP gene expression and impaired DNA repair especially defective homologous recombination DNA repair can be used as an indicator of tumor sensitivity to PARP inhibitor. Hence, in some embodiments, treatment of breast cancer can be enhanced not only by determining the HR and/or HER2 status of the cancer, but also by identifying early onset of cancer in BRCA and homologous recombination DNA repair deficient patients by measuring the level of PARP. The BRCA and homologous recombination DNA repair deficient patients treatable by PARP inhibitors can be identified if PARP is up-regulated. Further, such homologous recombination DNA repair deficient patients can be treated with PARP inhibitors”, see page 26, section 0178. PARP levels can be determined, see page 29, section 0200. Based on this disclosure, resistance to lone administration to a PARP inhibitor can also be tested.
Furthermore, Mateos-Gomez teaches breast cancer cells benefit from the inhibition of POLQ expression, see page 257, para. in col. 1. Mateos-Gomez teaches inhibitors for Polθ including shRNA target sequences, shPOLQ (human), see Figure 4 on page 256; and paragraph spanning both columns (cols.) on page 259. Cells with compromised HDR activity depend on this mutagenic polymerase for survival”, hence there is “…rationale for the development of Polθ -targeted approaches for cancer treatment”, see page 257, col.1.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to treat the HR-deficient cancer, including breast and ovarian cancers, with both, a PARP inhibitor and a Polθ inhibitor because the teachings of the references inform one of ordinary skill in the art assessing PARP activity and its relationship in HR-deficient cancer involve the same signaling pathway, see Sherman, page 26, section 0178; and entire Mateos-Gomez document. Moreover, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to combine the teachings of the references, which teach eliminating, reducing and/or depleting “…Polθ has a synergistic effect on cell survival in the absence of BRCA genes, suggesting that the inhibition of this mutagenic polymerase [Pol] represents a valid therapeutic avenue for tumours carrying mutations in homology-directed repair [HDR] genes”, see last sentence of Mateos-Gomez abstract.
As evidenced by Rodon and Spain, there is “…the need to treat cancers using drugs that target different members of the same pathway”, as well as combination therapy against distinct targets within the same pathway is beneficial, see PTAB decision, last para. on page 8; Rodon, page 41, col. 1, lines 6-14; page 1031, 2nd col., lines 9-12 and corresponding Figure 1 of Spain on page 1032 at close of instant rejection; and Gross page 1784, col. 1, sentences before Drug…segment. The evidence therein “…shows that the ordinary artisan would not have avoided using two drugs that address the same pathway, and indeed, would not even have been dissuaded from using two drugs targeting the same element in a pathway.”, see Decision, pages 8-10.
One of ordinary skill in the art would have been motivated to do so with a reasonable expectation of success by teachings in all references to administer inhibitors of both, PARP and Polθ because:
(1) PARP1 facilitates the recruitment of Polθ to double-stranded breaks (DSBs) repair and both are part of the same signaling pathway wherein HDR is compromised;
(2) “[a]dministration of a PARP inhibitor to women with a BRCA mutation may prove to be beneficial” and
(3) Mateos-Gomez provides direct evidence linking Polθ to alt-NHEJ repair in mammalian cells and makes clear “…cells with compromised HDR activity depend on this mutagenic polymerase for survival. Herein, all establish rationale for the development of combinatorial therapy for PARP1 and Polθ-targeted approaches for cancer treatment, see all references in their entirety and in particular, Sherman, page 38, section 0335; and Mateos-Gomez, see Figures 2 and 3 on page 255; paragraph bridging pages 255 and 256; Figure 4e on page 256; last paragraph on page 257; and Extended Data Figures 6 and 7.
PNG
media_image1.png
460
685
media_image1.png
Greyscale
Conclusion
7. Any inquiry concerning this communication or earlier communications from the Examiner should be directed to ALANA HARRIS DENT whose telephone number is (571)272-0831. The Examiner works a flexible schedule, however she can generally be reached 8AM-8PM, Monday through Friday.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the Examiner by telephone are unsuccessful, the Examiner’s supervisor, Julie Wu can be reached at 571-272-5205. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
ALANA HARRIS DENT
Primary Examiner
Art Unit 1643
14 May 2026
/Alana Harris Dent/Primary Examiner, Art Unit 1643
Prosecution Insights