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 .
Claim Objections
Claims 36-49 are objected to because of the following informalities: 1)The structures in claim 36 are not fully legible; 2) The SEQ ID NOs in claim 36 should be immediately next to each of the recited sequences or it is not clear which SEQ ID NO is directed to which sequence; 3) claim 39 recites PDR001 (Novartis) twice; and 4) Claim 49 does not end with a period.
An alternative for part 2) (above) is to recite the sequences followed by “SEQ ID NOs: 19 and 20, respectively”.
Appropriate correction is required. Claims 37-49 are objected to because they depend from claim 36.
Specification
The disclosure is objected to because of the following informalities: The SEQ ID NO should be immediately next to each of the recited sequences or it is not clear which SEQ ID NO is directed to which sequence. An alternative is to disclose the sequences followed by SEQ ID Nos: xx and xx, respectively. See pages 4, 7-14, 26, 33-40, and 53, for example.
Appropriate correction is required.
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 39 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 39 recites that the anti-PD-1 antibody is PDR001 (Novartis), Nivolumab (Bristol-Myers Squibb), Pembrolizumab (Merck & Co), Pidilizumab (CureTech), MEDI0680 (Medimmune), REGN2810 (Regeneron), TSR-042 (Tesaro), PF-06801591 (Pfizer), BGB-A317 (Beigene), BGB-108 (Beigene), INCSHR1210 (Incyte), AMP-224 (Amplimmune), IBI308 (Innovent and Eli Lilly), JS001, JTX-4014 (Jounce Therapeutics), PDR001 (Novartis) or MGA012 (Incyte and MacroGenics).
PDR001 was investigated by Novartis, but it is unclear what is meant by “PDR001 (Novartis)”. The specific structure required is not evident by recitation of “PDR001 (Novartis)”. PDR001 appears to be an internal research code rather than referring to a specific structure.
Nivolumab (Bristol-Myers Squibb) appears to be a generic name for Opdivo or Opdualag, which are trademarked brand names. Recitation of “Nivolumab (Bristol-Myers Squibb)” does not impart any specific structure for the protein.
Pembrolizumab (Merck & Co) is a generic name for Keytruda, which is a trademarked brand name. Recitation of “Pembrolizumab (Merck & Co)” does not impart any specific structure for the protein.
Recitation of “Pidilizumab (CureTech)” does not impart any specific structure for the protein.
Recitation of “MEDI0680 (Medimmune)” does not impart any specific structure for the protein. In fact, it appears to be a designation for a drug candidate developed by Astrazeneca. The specific structure required is not clear.
REGN2810 (Regeneron) is a generic name for Libtayo which is trademarked brand name for the drug cemiplimab. Recitation of “REGN2810 (Regeneron)” does not impart any specific structure for the protein.
TSR-042 (Tesaro) is a generic name for Jemperli which is trademarked brand name. Recitation of “TSR-042 (Tesaro)” does not impart any specific structure for the protein.
Each of the recited antibodies of claim 39 appear to recite clinical trial designations or alternate names of trademarked products. The specification does not disclose any specific structure required for each of the recited proteins and therefore the metes and bounds of the claim are not definite.
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 40-49 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 prostate, ovarian, and breast cancer via delivery of the instant conjugate (OX425), does not reasonably provide enablement for a method of treating any possible cancer via delivery of the instant conjugate alone. 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.
Factors to be considered in a determination of lack of enablement include, but are not limited to:
(A) The breadth of the claims;
(B) The nature of the invention;
(C) The state of the prior art;
(D) The level of one of ordinary skill;
(E) The level of predictability in the art;
(F) The amount of direction provided by the inventor;
(G) The existence of working examples; and
(H) The quantity of experimentation needed to make or use the invention based on the content of the disclosure.
In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988)
The instant claims are directed to a method of treating any possible cancer via delivery of the instant conjugate (OX425) via any mode of administration.
The specification demonstrates that OX425 demonstrates potent antitumor activity in prostate, ovarian, and triple negative breast cells in vitro (Example 11) and OX425 immune cells infiltration in the tumor microenvironment of EMT-6 breast cancer cells in xenografts (Example 15). The specification demonstrates treatment of breast cancer carcinoma in mice via intraperitoneal injection (Example 16).
The specification does not draw an adequate nexus between delivery of the instantly recited conjugate in vivo via any means and the predictable outcome of the treatment of any possible cancer. Each cancer type has different etiologic considerations and applicant has not demonstrated that the instant conjugate would predictably result in treatment effects in any type of possible cancer.
In breast cancer cells, the specification discloses that the activity of OX425 is through an increase in PARP activation. However, not any cancer can be treated by PARP agonism. For example, Chen (Chinese Anti-Cancer Association, 2011, 30, 7, 463-471) teaches that inhibitors of PARP preferentially kill cancer cells in BRCA-mutation cancer cell lines over normal cells. Also, PARP inhibitors increase cytotoxicity by inhibiting repair in the presence of chemotherapies that induces SSBs (abstract). Since PARP inhibition is utilized to treat particular cancers, certainly an increase in PARP via delivery of the instant conjugate would not treat any possible cancer as claimed.
Chalmers et al. (British Medical Bulletin 2009; 89: 23–40) teach that potent and specific inhibitors of PARP are available; these have been shown to increase the cytotoxicity of a range of anti-cancer agents including temozolomide, irinotecan and radiation (page 23). Chalmers et al. teach that there is a particularly promising role for PARP inhibitors in the treatment of malignant brain tumors (page 23). Therefore, PARP activation would not be expected to treat this cancer type.
Additionally, the specification discloses that specific concentrations were required for the agonistic effect on PARP, although the instant claims are not limited to any specific concentration for the treatment of any specific cancer type. The specification discloses that OX425 induced a high antitumor activity with the majority of IC50s ranging from 10 to 300 nM (Figure 9A), which is not required by the instant claims. Figure 9A demonstrates a large difference in percent survival depending upon the concentration of OX425.
The scope of the claims in view of the specification as filed together do not reconcile the unpredictability in the art to enable one of skill in the art to make and/or use the claimed invention, namely a broad method of treating any possible cancer encompassing in vivo effects.
MPEP 2164.01
Any analysis of whether a particular claim is supported by the disclosure in an application requires a determination of whether that disclosure, when filed, contained sufficient information regarding the subject matter of the claims as to enable one skilled in the pertinent art to make and use the claimed invention.
Also, MPEP 2164.01(a)
A conclusion of lack of enablement means that, based on the evidence regarding each of
the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed
invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27
USPQ2d 1510, 1513 (Fed. Cir. 1993).
Given the teachings of the specification as discussed above, one skilled in the art could not predict a priori whether introduction of the instant conjugate alone via any mode of delivery and at any concentration in vivo by the broadly disclosed methodologies of the instantly claimed invention, would result in successful treatment of each species of cancer. To practice the claimed invention, one of skill in the art would have to de novo determine; the stability of the conjugate molecule in vivo, delivery of the conjugate molecule to the whole organism, specificity to the target tissue in vivo, dosage and toxicity in vivo, and entry of the molecule into the cell in vivo and the effective action therein. Without further guidance, one of skill in the art would have to practice a substantial amount of trial and error experimentation, an amount considered undue and not routine, to practice the instantly claimed invention.
A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation (see MPEP 2164.01(a)).
Claim Rejections - 35 USC § 103
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 (i.e., changing from AIA to pre-AIA ) 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 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.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 36-49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Sproat et al. (WO 2020/127965 A1), in view of Damha et al. (WO 2007/048244 A2) and Damha et al. (WO 02/20773 A2).
Sproat et al. teach a conjugated nucleic acid molecule wherein the nucleic acid molecule comprises instant SEQ ID NOs: 19 and 20 and the structure recited in instant claim 1 (see page 6). The only difference between the conjugate on page 6 of Sproat et al. and instant claim 36 is the placement of phosphorothioate and FANA modifications (instant claims 36 and 37).
However, the conjugate structures on pages 6-11 of Sproat et al. comprise various combinations of phosphorothioates (denoted as s) and FANA modifications (denoted by italics).
Sproat et al. teach that in a particular aspect, the conjugated nucleic acid molecules have at least one, two, three or more 2'-deoxy-2’-fluoroarabinonucleotides (FANA). FANA adopts a DNA-like structure resulting in an unaltered recognition of the conjugated nucleic acid molecules by the proteins of interest.
Sproat et al. teach that 0X401, 0X410 and 0X411 having a modified phosphodiester backbone such as a phosphorothioate linkage (0X401) or both phosphorothioate linkage and FANA modifications (0X410, OX411) on the three first nucleotides on the 3’ and/or 5’ strands, have similar affinities (K.sub.D) and kinetics of association (k.sub.on) with PARP-1. 0X402 having a phosphorothioate linkage on the three first nucleotides on the 3’ and/or 5’ strands, has similar affinity of association with PARP-1 than above mentioned molecules, but has a lower kinetic of association with PARP-1 (page 69).
Additionally, Damha et al. teach small interfering RNA (siRNA) duplexes that inhibit gene expression containing at least one arabinose modified nucleotide, more specifically a more 2'-deoxy-2’-fluoroarabinonucleotides (FANA) (abstract).
Damha et al. teach that duplex may have any number of the arabinonucleotides at any location at either the sense or antisense strand ([0009] and Table 1). Damha et al. discloses varying quantities and locations of the arabinonucleotides including full modification (page 6).
Damha et al. teaches incorporation of phosphorothioate modifications [0014]. Damha et al. teaches that incorporation of the arabinonucleotides, preferably FANA, increases nuclease stability [0015][0029].
Damha et al. is considered to be additional evidence that it was known to incorporate FANA and phosphorothioate modifications at varying quantities and positions with an expectation of increased stability in the presence of nucleases, which would be desired for the instantly recited conjugate containing a double stranded oligomer.
Damha et al. (WO 02/20773 A2) teach incorporation of FANA nucleotides into DNA antisense oligonucleotides (page 1) for increase in stability in the presence of nucleases (page 2). Damha et al. also teaches that phosphorothioate modifications are more stable than those with phosphodiester linkages (page 2).
Damha et al. (WO 02/20773 A2) teach incorporation of FANA residues in gapmer configurations flanking a DNA segment (page 8), wherein the gap portion comprises phosphorothioates (page 11 and Table1).
Sproat et al., Damha et al., and Damha et al. (WO 02/20773 A2) are evidence that it was known to incorporate FANA modifications at varying quantities and positions of DNA and RNA nucleic acid therapeutics to increase stability in the presence of nucleases.
The specific quantity and placement is considered to be a matter of design choice.
It is noted that claim 37 only recites optional elements and therefore does not require anything in addition to the requirements of claim 36.
Sproat et al. teaches a pharmaceutical composition comprising the conjugate and further comprising an immune checkpoint inhibitor (page 11) (instant claims 38, 42, and 43). Sproat et al. teaches that an exemplary PD-1 antibody is Nivolumab (page 46). Sproat et al. teaches that the immune checkpoint molecule can be Novartis, a PD-L1 inhibitor (page 47) (instant claims 39 and 44-47).
Sproat et al. teach a method of treating cancer by administering to a patient in need thereof a conjugated nucleic acid molecule of the present invention in combination with a chemotherapeutic, radiotherapeutic, or anti-angiogenic agent (page 51) (instant claim 40).
Sproat et al. teach selection of Signma-2 receptor ligands to facilitate endocytosis to target cancer cells, more specifically malignant cancer cells (breast, ovarian, lung, brain, bladder, colon, and melanoma) (page 35) (instant claim 41).
Sproat et al. teach that the molecule is for use in the treatment of cancer (page 42) wherein the cancer is head and neck, lymphoma, leukemia, sarcoma, melanoma, kidney, ovarian, pancreatic, prostrate, lung, thyroid, esophageal, bladder, breast, liver, colorectal, endometrial, or cervical (page 43)(instant claim 41).
Although Sproat et al. does not specifically teach that the cancer is a homologous recombination deficient or proficient tumor, Sproat et al. teaches that the cancer is each of the instantly recited species of cancers in instant claim 41. Additionally, Sproat et al. teach: Homologous recombination (HR) repair pathway is an error-free repair pathway essential to maintain genetic stability and intact DNA information. HR is a well-organized multi-step machinery that consume a large amount of cellular energy. As 0X401 triggers a high NAD.sup.+ consumption and therefore induces a metabolic disequilibrium in tumor cells (Example 9), inventors demonstrated that it could disturb the HR repair machinery very dependent of energy (Example 10). Therefore, Sproat et al. teaches that the conjugate disturbs the HR repair machinery and induces a metabolic disequilibrium in tumor cells. It would have been obvious for the cancer to be a homologous recombination deficient or proficient tumor as a matter of design choice because the conjugate was known to induce a metabolic disequilibrium in tumor cells via disturbing the homologous recombination repair pathway (instant claims 48 and 49).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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/AMY ROSE HUDSON/ Primary Examiner, Art Unit 1636