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 .
Claims 1-9, 12, 14-22, 24, 40, 44-46, 59, 62, 65 ,71, 75-77 and 82 are pending and will be examined on the merits.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claim 24 is 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 methods of treating a cancer, does not reasonably provide enablement for methods of preventing a cancer. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re wands, 858 F.2d 731, 737.8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
The instant claims are drawn to a method for treating or preventing a cancer in a subject in need thereof, said method comprising administering to said subject a composition comprising a nucleic acid molecule conjugated to one or more therapeutic agents, wherein the nucleic acid targeting molecule targets a lysosome of a tumor associated macrophage.
When given the broadest reasonable interpretation, “a subject in need thereof” includes humans and non-experimental animals.
The Merriam-Webster definition of the word “prevent”—“to keep from happening or existing”. Thus, the broadest reasonable interpretation of the claim is that the method comprising the administration of the instant claimed nucleic acid targeting molecule/therapeutic agent(s) conjugate described in the preceding paragraph prophylactically prevents cancer from occurring by killing every cancer cell present or stopping every healthy cell from becoming cancerous.
The skilled artisan recognized that before any method of preventing a particular cancer could be practiced with any level of predictability, some method of identifying subjects predisposed to the particular cancer must be available. While the art has advanced in recent years, it is still highly unpredictable not only which individuals will develop a particular cancer, but also when a “preventative” therapy will be helpful.
Breast cancer illustrates the difficulties associated with detecting and preventing cancer. The skilled artisan generally recognized symptoms of breast cancer to include changes in the breast such as the presence of a lump, nipple discharge, or other changes in the shape or texture of the breast. However, such symptoms are non-specific and have multiple other potential causes. Even detection of a breast mass by mammography is only an early step in the diagnosis of breast cancer. As noted in a 2014 article in the World Journal of Clinical Oncology, following an abnormal mammographic finding exam, biopsy is required for a diagnosis (cancer vs. benign lesion) and staging is required to determine appropriate treatment (Shah, et al.World J Clin Oncol 2014 August 10; 5(3): 283-298, Table 1).
Further, even in individuals judged to have a twofold increased risk of developing breast cancer, prevention with tamoxifen was incomplete. Briefly, high risk women were given either tamoxifen or a placebo and the occurrence of breast cancer was monitored for 20 years. The placebo group had a breast cancer rate of 12.3% and the treatment group had a breast cancer rate of 7.8 %. (Cuzick, et al Lancet Oncol 2015 Jan; 16(1) 67-75, Results, page 4). While tamoxifen did reduce the risk of the occurrence of breast cancer, it did not completely prevent it. It should be noted that the Specification is not enabling for prevention of any type of cancer.
Claims 1-8, 12, 14-22, 24, 40, 44-46, 59, 62, 65 ,71, 75-77 and 82 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention. This is a written description rejection.
All of claims 1-8, 12, 14-22, 24, 40, 44-46, 59, 62, 65 ,71, 75-77 and 82 contain the limitation of a nucleic acid targeting module with the recited function of targeting the lysosome of a macrophage, which is recited in claims 1, 24, 40, 44, 59, 62, 65, 71, 75-77 and 82, creating the required function that the nucleic acid targeting module recited in these claims bind to or target the lysosome of a macrophage.
With respect to the structure of the macrophage lysosome-targeting nucleic acid targeting module, claims 3 and 4 recite nucleic acid structure classes (e.g. dsDNA, ssRNA, etc…) for the nucleic acid targeting module. Claim 5 further limits claim 3 by specifying that the nucleic acid targeting molecule is 38 base pairs. Claim 6 recites the structural limitation that nucleic acid targeting module comprise two single stranded nucleic acid molecules that are fully or partially complementary to one another. Claims 7 and 8 further limit claim 6 by specifying specific lengths for the two single stranded nucleic acids recited in claim 6. None of the claims subject to this rejection, however, provide nucleic acid sequences required to permit the nucleic acid targeting molecule to perform the required function of targeting a lysosome of a macrophage.
The instant Specification does disclose the complete structure of several nucleic acid targeting modules of several nucleic acid classes as well as data demonstrating that these nucleic acid targeting modules are capable of performing the required function of targeting a lysosome of a macrophage, which are: dsDNA (SEQ ID NO: 40 paired with one of SEQ ID NOs: 41 or 42), ssDNA (SEQ ID NO: 41), dsRNA (SEQ ID NO: 43 paired with SEQ ID NO: 44), ssRNA (SEQ ID NO: 43) and ssDNA:ssRNA (SEQ ID NO: 45 paired with SEQ ID NO: 46) (Specification, ¶ 0053; Fig. 1). Please note that this is a disclosure of eight distinct nucleic acid targeting modules capable of performing the required function of targeting the lysosome of a macrophage.
Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) teaches on the subject of CpG oligonucleotides as targeting agents (Nechaev, Abstract). Nechaev teaches that that CpG-siRNA conjugates, which comprise CpG oligonucleotides that are TLR9 ligands, interact with TLR9+ macrophages, the conjugate is first endocytosed into an early endosome, where TLR9 facilitates the release of siRNA coupled with the concomitant migration of the endosome to the cell’s nucleus and with the portion of conjugate remaining in the endosome being subject to lysosomal degradation (Nechaev, Graphical Abstract; reproduced below):
PNG
media_image1.png
632
1079
media_image1.png
Greyscale
The written description requirement may be satisfied in one of two ways: by disclosure of a representative number of species or by establishment of structure/function correlation (See MPEP § 2163). The instant Specification does disclose the eight examples of species of nucleic acid targeting modules capable of performing the required function of targeting the lysosome of a macrophage. However, when there is substantial variation within a genus, one must describe a sufficient variety of species to reflect the variation within that genus (See: MPEP § 2163(II)(3)(a)(ii)). As such, species disclosed in the instant specification are not sufficient to establish written description for the claimed genera as a disclosure of eight species of nucleic acid targeting modules is not representative of the claims, which are directed to any nucleic acid targeting module of any sequence capable of targeting a lysosome of a macrophage.
With respect to structure-function correlation, the teachings of Nechaev show that, at the time of filing, it was known that CpG oligonucleotides were known nucleic acid modules that were known to be capable of targeting the lysosome of a macrophage. However, this is also due to the known and specific interaction between CpG oligonucleotides and TLR9. The claims subject to this rejection are directed to any nucleic acid targeting molecule of any sequence capable of performing the recited function of targeting a lysosome of a macrophage. Knowledge that CpG oligonucleotides are nucleic acid targeting modules capable of performing the required function of targeting a lysosome of a macrophage does not establish structure-function correlation that would permit a skilled artisan to envision, a priori, the required sequence/structure non-CpG nucleic acid targeting modules would need to have in order to perform the required function of targeting the lysosome of a macrophage. There is nothing in the instant Specification to supplant this notion.
Because the species disclosed are insufficient to be considered representative of any the scope of any of the genera encompassed in the rejected claims coupled with the lack of established structure/function correlation, claims 1-8, 12, 14-22, 24, 40, 44-46, 59, 62, 65 ,71, 75-77 and 82 lack written description and Applicant was not in possession of the invention as claimed.
Claim Rejections - 35 USC § 102
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 1-3, 12, 21-22, 24, 59, 62, 71 and 75-77 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307).
Yu discloses multifunctional compositions that are capable of being delivered to cells of interest for the treatment of diseases and for the improvement of immune function (Yu, Abstract). Yu discloses compositions comprising multifunctional molecules that are capable of being delivered to cells of interest for the treatment of diseases (including cancer, infectious diseases and autoimmune diseases) (Yu, ¶ 0003) Yu teaches that signal transducer and activator of transcription 3 (STAT3) is activated at high frequency in diverse cancers and that blocking STAT3 in tumor cells induces apoptosis, inhibits angiogenesis, abrogates metastasis and activates antitumor immune responses (Yu, ¶ 0005). Yu teaches that the multifunctional molecules of Yu are chimeric molecules comprising an active oligonucleotide that is a TLR ligand and an active agent, wherein said chimeric molecules are taken up and internalized by immune cells and malignant cells, allowing actions of both the TLR ligand and the active agent (Yu, ¶ 0009).
Yu teaches that the TLR9 ligand-siRNA conjugate of Yu comprises a delivery moiety that is an oligonucleotide ligand for a TLR (same as a nucleic acid targeting module with one or more therapeutics attached) and one or more active agents including: 1) activating dsRNA, 2) siRNA, 3) a small molecule or 4) a peptide (Yu, ¶ 0010). Regarding claim 3, Yu also teaches that the TLR9 ligand of Yu is a CpG ODN oligonucleotide (a ssDNA oligonucleotide) (Yu, ¶ 0045). Regarding claim 2, Yu also teaches that the CpG ODN targeting module of Yu and the siRNA module of Yu may be linked covalently (Yu, ¶ 0050-0054). Yu also teaches that any element of the multimeric molecule of Yu (e.g., the delivery moiety, the active agent(s), etc…) may include labels that are fluorescent or radionuclides to promote detection using active or passive detection of electromagnetic emissions (Yu ¶ 0011). Please note that the inclusion of the labeling agent of Yu additionally reads on the “labeling module” structural limitations of claims 21-22, 71. Regarding claim 24, Yu teaches that Mice bearing MCP11 tumors were administered the CpG-STAT3 siRNA of Yu, which demonstrated in vivo treatment with CpG-STAT3 siRNA resulted in significant tumor growth inhibition (Yu, ¶ 0131). Regarding claims 75-77, Yu teaches that B16 tumor-bearing mice were administered the FITC-labeled CpG-STAT3 siRNA, the mice were then anesthetized and the labels were detected in intravital two-photon imaging (an in vivo technique) (Yu, ¶ 0118).
Additionally, Nechaev provides evidence that CpG-siRNA conjugates interact with TLR9+ macrophages, the conjugate is first endocytosed into an early endosome, where TLR9 facilitates the release of siRNA coupled with the concomitant migration of the endosome to the cell’s nucleus and with the portion of conjugate remaining in the endosome being subject to lysosomal degradation (Nechaev, Graphical Abstract; reproduced below):
PNG
media_image1.png
632
1079
media_image1.png
Greyscale
As such, Nachaev provides sufficient evidence to demonstrate that when the CpG-siRNA conjugate of Yu is internalized by a TLR9+ macrophage, the molecule will always be targeted to a lysosome of a macrophage, because lysosomal degradation is the ultimate fate of such conjugates when endocytosed by TLR9+ macrophages and is sufficient to read on the “target a lysosome of a macrophage” structural limitations. Regarding claim 62 specifically, Nachaev also provides sufficient evidence to demonstrate that administering the CpG-ODN/STAT3 siRNA conjugate of Yu will always inherently minimize side effects associated with the siRNA therapeutic agent because release of the STAT3 siRNA from the conjugate of Yu requires the presence of TLR9 and, as such, any side effects associated with the STAT3 siRNA would be limited to cells expressing active TLR9. As such, this evidence is sufficient to demonstrate that the administration of the TLR9 targeting CpG/STAT3 siRNA conjugate of Yu taught by Yu at ¶ 0131 of the Yu reference minimized the side-effects of the STAT3 siRNA compared to systemic administration of STAT3 siRNA alone.
Claim Rejections - 35 USC § 103
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) 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 12, 21-22, 24, 59, 62, 71 and 75-77 above and in further consideration of the Yu reference.
The teachings of Yu are discussed above. Yu also teaches that activated STAT3 both promotes a wide range of genes critical for angiogenesis and also inhibits expression of multiple genes that are anti-angiogenic and whose upregulation are critical (Yu, ¶ 0006). Yu also teaches that TLR9 ligand- STAT3 siRNA conjugate of Yu are used in methods of treating disease due to excessive angiogenesis, wherein said disease is diabetic retinopathy (Yu, ¶ 0027). Additionally, Yu also teaches that the novel molecules of Yu comprise multifunctional linkers, allowing for one first moiety that directs cell or tissue-specific delivery of one or more secondary moieties that are active agents for treating cancer (Yu, ¶ 0041). In addition, Yu teaches that the CpG oligonucleotides of Yu are oligonucleotides containing a CpG motif that are between 2 and 100 bp in length (Yu, ¶ 0036).
Yu does not explicitly teach the TLR9 targeting CpG/STAT3 siRNA conjugate of Yu further comprises a secondary therapeutic agent that is an anticancer agent. Yu does not teach that the CpG nucleic acid component of the conjugates of Yu are 38 base pairs in length. Yu does not explicitly teach a method of treating diabetes in a subject in need thereof, said method comprising administering a nucleic acid-targeting molecule and one or more therapeutic agents attached, wherein the targeting module targets the therapeutic agents to the lysosome of a macrophage.
It would be prima facie obvious to one of ordinary skill in the art to administer the multifunctional, STAT3 inhibiting molecules of Yu in a method of treating diabetic retinopathy. One of ordinary skill in the art would be motivated to do this in order to better treat diabetic retinopathy. One of ordinary skill in the art would have a reasonable expectation of success administering the multifunctional, STAT3 inhibiting molecules of Yu in a method of treating diabetic retinopathy because: 1) Yu teaches that active STAT3 both upregulates pro-angiogenic genes and suppresses anti-angiogenic genes, 2) the multifunctional molecules of Yu comprise a STAT3 inhibiting moiety, 3) Yu teaches that the multifunctional molecules of Yu are administered in methods of treating diseases due to excessive angiogenesis, with diabetic retinopathy being an exemplary disease treatable via the multifunctional molecules of Yu. This additionally reads on claim 40.
It would be prima facie obvious to one of ordinary skill in the art to start with the CpG length range between 2 and 100 bp taught by Yu and arrive at a composition wherein both the CpG nucleic acid is 38 nucleotides in length via routine experimentation. One of ordinary skill in the art would be motivated to do this in order to optimize the TLR9 binding properties of the CpG component of the conjugates of Yu. One of ordinary skill in the art would have a reasonable expectation of success starting with the length range between 2 and 100 bp taught by Yu and arriving at a composition wherein both the CpG nucleic acid is 38 nucleotides in length via routine experimentation because: 1) Yu teaches CpG lengths between 2 and 100 bp and 2) starting with ranges of nucleotide lengths disclosed in the prior art and arriving at optimized nucleotide lengths within their respective disclosed range is well within the purview of one of ordinary skill in the art.
Additionally, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). Please note that this modification additionally reads on claim 5.
It would be prima facie obvious to one of ordinary skill in the art to modify the composition of Yu, said composition comprising a CpG targeting oligonucleotide and a STAT3 inhibiting siRNA to comprise an additional therapeutic agent that is an anticancer therapeutic. One of ordinary skill in the art would be motivated to do this in order to enhance the anticancer functionality of the TLR9 ligand-siRNA conjugate of Yu. One of ordinary skill in the art would have a reasonable expectation of success modifying the CpG oligonucleotide-siRNA conjugate of Yu to comprise an additional anticancer therapeutic because Yu teaches one or more therapeutic agents linked to the targeting moiety and one of ordinary skill in the art would reasonably deduce that inclusion of a second anticancer therapeutic would provide an additional anticancer effect that is at least additive. Please note that this additionally reads on claims 45-46.
Claim(s) 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 65, 71 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 above and in view of Tvardi (Tvardi, Inc; US Clinical Trial NCT03195699; First Published 11/15/2017);
The teachings of Yu are discussed above. In addition, Yu also teaches that the immune modulation induced by concomitant TLR9 activation and siRNA silencing of STAT3 is a strongly synergistic immune response in a murine B16 melanoma model, wherein CpG alone, STAT3 siRNA alone and CpG conjugated to scrambled siRNA were not able to induce significant antitumor responses but the chimeric molecule comprising both TLR9-targeting CpG and STAT3 targeting siRNA elicited a potent antitumor response (Yu, ¶ 0096; Fig 3a-e).
Yu does not teach a method of sensitizing a melanoma patient to the therapeutic STAT3 inhibitor TTI-101, said method comprising administering a composition TLR9 ligand/STAT3 conjugate of Yu and further comprising TTI-101, wherein the administration of TLR9 ligand/STAT3 siRNA of Yu sensitizes the subject to TTI-101.
Tvardi teaches the STAT3 inhibitor TTI-101 was under evaluation as an in-human anti-melanoma therapeutic in mid-November 2017 (Tvardi, p 1, ¶ 1-2)
It would be prima facie obvious to one of ordinary skill in the art to combine the TLR9 Ligand/STAT3 siRNA conjugate of Yu and the TTI-101 of Tvardi to form a method of sensitizing a melanoma patient to the therapeutic STAT3 inhibitor TTI-101, said method comprising administering a composition TLR9 ligand/STAT3 conjugate of Yu and further comprising TTI-101, wherein the administration of TLR9 ligand/STAT3 siRNA of Yu sensitizes the subject to TTI-101. One of ordinary skill in the art would be motivated to do this in order to better treat melanoma. Yu teaches that the TLR9 ligand STAT3 siRNA conjugate of Yu is useful in methods of treating melanoma. Yu also teaches combining TLR9 agonism with STAT3 inhibition elicits a synergistic, greater than additive anti-tumor response. Tvardi teaches that the STAT3 inhibitor TTI-101 was being studied as an in-human anti-melanoma therapeutic well before the effective filing date of the instant application. One of ordinary skill in the art would have a reasonable expectation of success sensitizing a melanoma patient to the therapeutic STAT3 inhibitor TTI-101, said method comprising administering the TLR9 ligand/STAT3 conjugate of Yu and further comprising administering TTI-101, wherein the TLR9 ligand/STAT3 siRNA of Yu sensitizes the subject to TTI-101 because: 1) Yu teaches that the TLR9 ligand/STAT3 siRNA of Yu is useful for the treatment of melanoma, 2) Tvardi teaches that TTI-101 is also useful for the treatment of melanoma, 3) Yu teaches that TLR9 agonism works in concert with the STAT3 inhibitors to produce an anti-tumor response far greater than the sum of the two monotherapies and 4) one of ordinary skill in the art would reasonably deduce that this greater than additive effect would be observed when TTI-101 is administered because TTI-101 is a STAT3 inhibitor.
Claim(s) 1-3, 5, 12, 14, 20-22, 24, 40, 44-46, 59, 62, 71 and 75-77 are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 above and in view of Bradley (Bradley, et al., J. Clin. Invest 2007 117(8):2337).
The teachings of Yu are discussed above.
Yu does not teach a method of treating atherosclerosis in a subject, said method comprising administering the macrophage-targeting TLR ligands of Yu linked to the LXR agonist GW3965.
Bradley teaches that liver X receptors (LXR-alpha and LXR-beta) are transcriptional regulators of cholesterol homeostasis and potential targets for antiatherosclerosis drugs (Bradley, Abstract). Bradley teaches that LXR-beta is expressed ubiquitously while LXR alpha is predominantly expressed in cells playing important roles in lipid homeostasis, such as macrophages (Bradley, p 2337, ¶ 2). Bradley teaches that ligand activation of LXRs have been reported to induce cholesterol efflux from lipid-laden peripheral cells such as macrophages (Bradley, p 2337, ¶ 3). Bradley teaches that the LXR pathway plays a direct role in atherosclerosis susceptibility with LXR-alpha/LXR-beta double knockouts exhibit increased cholesterol accumulating in the arterial wall macrophages on mice fed a normal diet, whereas single knockouts of LXR-alpha or LXR-beta alone do not display this phenotype, indicating the two isotypes can compensate for one another (Bradley, p 2337, ¶ 3). Bradley teaches that while endogenous ligands acting on LXR-beta are unable to provide sufficient macrophage cholesterol efflux to maintain homeostasis in LXR-alpha/apoE double knockout mice, the synthetic LXR agonist GW3965 was able to significantly inhibit the development of atherosclerotic lesions and significantly decrease lesion area in LXR-alpha/apoE double knockout mice, indicating the LXR-beta-targeting GW3965 is able to compensate for the loss of LXR alpha (Bradley, p 2341, ¶ 2).
It would be prima facie obvious to one of ordinary skill in the art to combine the macrophage-targeting CpG nucleotide conjugate of Yu with the GW3965 LXR agonist of Bradley to form a CpG nucleotide-GW3965 conjugate that is administered in methods of treating atherosclerosis. One of ordinary skill in the art would be motivated to do this in order to better treat atherosclerosis. One of ordinary skill in the art would have a reasonable expectation of success combining the macrophage-targeting CpG nucleotide conjugate of Yu with the GW3965 LXR agonist of Bradley to form a CpG nucleotide-GW3965 conjugate that is administered in methods of treating atherosclerosis because: 1) Bradley teaches that LXR-alpha is predominantly expressed on cells associated with lipid homeostasis such as macrophages, 2) Bradley also teaches that the LXR-beta activating drug GW3965 is able to induce sufficient cholesterol efflux from macrophages to compensate for atherosclerosis induced by lack of LXR-alpha functionality and 3) one of ordinary skill in the art would reasonably deduce that the macrophage-targeting functionality provided by the macrophage-targeting polynucleotide of Yu would enhance the activity of GW3965 because the polynucleotide of Yu would preferentially direct the GW3965 of Bradley to macrophages, which where the GW3965 of Bradley needs to be in order to induce the anti-atherosclerotic cholesterol efflux from macrophages.
Claim(s) 1-3, 5, 12, 14, 19, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 above and in view of Sagiv-Barfi (Sagiv-Barfi, et al., Blood 2015 125(13):2079).
The teaching of Yu are discussed above.
Yu does not teach a conjugate comprising TLR9 CpG ligands of Yu attached to an active agent that is the BTK inhibitor ibrutinib.
Sagiv-Barfi teaches that concomitant administration of intratumorally injected TLR9 activating CpG polynucleotide and systemic ibrutinib resulted in the complete eradication of tumors at the CpG injection site as well as distant sites in a murine lymphoma model (Sagiv-Barfi, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to combine the TLR9 CpG polynucleotide ligand of Yu attached to the ibrutinib of Sagiv-Barfi. One of ordinary skill in the art would be motivated to do this in order to better treat lymphoma. One of ordinary skill in the art would have a reasonable expectation of success combining the TLR9 CpG polynucleotide ligand of Yu attached to the ibrutinib of Sagiv-Barfi and administering the resultant conjugate in methods of treating lymphoma because: 1) Sagiv-Barfi teaches concomitant administration of ibrutinib and TLR9 activating CpG oligonucleotide elicits strong antitumor synergistic effects, 2) The targeting moiety of Yu is a TLR9 CpG polynucleotide and 3) one of ordinary skill in the art would reasonably deduce that linking the ibrutinib of Sagiv-Barfi to the CpG of Yu would further increase the synergistic anti-tumor action(s) of the two moieties by ensuring that the two moieties are located in close proximity to each other and thus would be more likely to act in concert with each other.
Claim(s) 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71, 75-77 and 82 is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 above and in further view of Thomalla (Thomalla, et al, J. Endocrinology 2019 240:325-343).
The teachings of Yu are discussed above.
Yu does not teach a method of imaging a biological phenomenon associated with obesity in a subject in need thereof comprising administration of a composition comprising a nucleic acid targeting molecule and one or more labeling molecules attached to the nucleic acid, wherein the nucleic acid targets a lysosome of a macrophage.
Thomalla teaches on the subject of toll like receptor 9 in adipocytes as well as TLR9 expression during adipocyte differentiation (Thomalla, Abstract). Thomalla teaches that TLR9 gene expression is induced during adipocyte differentiation, with no detectable TLR9 mRNA in pre-adipocytes but a stepwise increase of TLR7 mRNA during differentiation into mature adipocytes (Thomalla, p 330, ¶ 3; Fig 1A-D). Thomalla also teaches that adipocyte lipid accumulation is dependent on intact TLR9 with TLR9-inhibitory siRNA significantly reducing adiponectin mRNA expression levels (Thomalla, p 330, ¶ 4, Fig. 2A-D).
It would be prima facie obvious to one of ordinary skill in the art to use the CpG oligonucleotide comprising a fluorescent or radionuclide label of Yu to image adipocyte differentiation (a biological phenomenon associated with obesity) in a method comprising administering the labeled oligo of Yu and detecting the label in view of the teaching of Thomalla. Thomalla teaches that TLR9 expression levels positively correlate with adipocyte differentiation and that adipocyte differentiation requires active TLR9 presence. One of ordinary skill in the art would have a reasonable expectation of success using the CpG oligonucleotides comprising a fluorescent or radionuclide label of Yu to image adipocyte differentiation in a method comprising administering the labeled oligo of Yu and then detecting the label because: 1) Thomalla teaches that TLR9 expression levels positively correlate with adipocyte differentiation, 2) the CpG oligonucleotide component of the labeled CpG of Yu is a ligand to TLR9 and 3) the fluorescent or radionuclide label component of the labeled CpG of Yu provides a detectable label the TLR9/CpG complex. Please note that this combination reads on all of claims 75-77 and 82
Claim(s) 1-3, 5, 12, 14-17, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 /are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 above and in further view of Martinez-Fabregas (Martinez-Fabregas, et al., Nature Communications 2018 9 article 5343).
The teachings of Yu are discussed above.
Yu does not teach a composition comprising the TLR-targeting CpG oligonucleotide of Yu coupled to both the cathepsin inhibitors E64 and pepstatin A.
Martinez-Fabregas teaches on the subject of STAT3 activation and lysosomal endopeptidases (Martinez-Fabregas, Abstract). Martinez-Fabregas teaches that cells respond to loss of asparagine endopeptidase (AEP) or other cysteine proteases by de novo expression of multiple hydrolases in a STAT3 mediated process (Martinez-Fabregas, abstract). Martinez-Fabregas teaches that lysosomal proteolytic activity relies on three enzyme families: cysteine proteases (cathepsins B and L), aspartyl proteases (cathepsin D and E) and a distinct cysteine protease known that is AEP (Martinez-Fabregas, p 2, ¶ 2). Martinez-Fabregas teaches that chronic or acute AEP-deficient promotes STAT3-dpendent transcription of all three families, including AEP itself (Martinez-Fabregas, p2, ¶ 3). Martinez-Fabregas also teaches that the primary driver of Jak2-STAT3 activation is ls associated with hyperproliferative disease and loss of kidney function in AEP-null mice (Martinez-Fabregas, p 2, ¶ 3). Martinez-Fabregas also teaches that treatment of WT MEF cells with the cysteine protease E64 or the aspartyl cathepsin inhibitor pepstatin A administered alone both induce activated STAT3 as well as multiple cathepsin proteases (Martinez-Fabregas, p 8, ¶ 2-4)
It would be prima facie obvious to one of ordinary skill in the art to form a composition comprising the TLR9-targeting CpG ODN of Yu linked to both cathepsin inhibitors E64 and pepstatin A ana administer the resultant molecule to a subject having AEP deficiency. One of ordinary skill in the art would be motivated to do this in order to simultaneously attenuate the increased STAT3 activation and increased proteolytic expression that are both caused by AEP deficiency. One of ordinary skill in the art would have a reasonable expectation of success form a composition comprising the TLR9-targeting CpG ODN of Yu linked to both cathepsin inhibitors E64 and pepstatin A ana administer the resultant molecule to a subject having AEP deficiency because: 1) Yu teaches that the TLR9 activating property of the CpG component of the multifunctional molecules of Yu works to counteract many effects caused by active STAT3, 2) Martinez-Fabregas teaches that AED deficiency leads to increased STAT3 activation and increased expression of all three classes of lysosomal proteases and 3) one of ordinary skill in the art would reasonably deduce that a TLR9 CpG moiety conjugated to both E64 and pepstatin A would counteract the effects of AED deficiency in multiple ways, with the E64 targeting the increased cysteine proteases, the pepstatin A targeting the upregulated aspartyl proteases and the CpG ODN counteracting the increased STAT3.
Claim(s) 1-3, 5, 12, 14, 18, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 and above and in further view of Le (Le, et al., Proc. Natl Acad Sci USA 2010 107(5):2037).
The teachings of Yu are discussed above. In addition to the teachings of Yu that are discussed above, Yu also teaches that CpG-STAT3 siRNA is easy taken up by both murine and human malignant B cells, including lymphoma, and that internalization of the CpG-STAT3 siRNA molecule of you leads to silencing of STAT3, which is accompanied by cell cycle arrest and tumor growth inhibition (Yu, ¶ 0098).
Yu does not teach the composition of Yu wherein the TLR9-targeting CpG oligonucleotide of Yu is conjugated to the LDHA inhibitor FX11.
Le teaches that many cancer cells avidly take up glucose and generate lactic acid dehydrogenase A (LDHA) (Le, abstract). Le teaches the reduction of LDHA by its small molecule inhibitor FX11 both reduced ATP levels and significant oxidative stress and cell death and also inhibited the progression of sizable human lymphoma xenografts (Le, Abstract). Le also teaches that this means inhibition of LDHA with FX11 is an achievable and tolerable treatment for LDHA-dependent tumors (Le, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to conjugate the FX11 of Le to the TLR9-targeting CPG ODN-STAT3 siRNA molecule of Yu with the net result being CpG-ODN that is covalently linked to both the STAT3 siRNA of Yu and the FX11 of Li that is administered in methods of treating lymphoma. One of ordinary skill in the art would have a reasonable expectation of success conjugating the FX11 of Le to the TLR9-targeting CPG ODN-STAT3 siRNA molecule of Yu with the net result being CpG-ODN that is covalently linked to both the STAT3 siRNA of Yu and the FX11 of Li that is administered in methods of treating lymphoma because: 1) Le teaches that FX11 inhibits lymphoma growth but also generates significant oxidative stress and cell death, 2) the CpG-ODN targeting nucleic acid of Yu is taken up rapidly by lymphoma cells and 3) conjugating a therapeutic agent with significant off-target side effects (such as LX11) to a targeting molecule that directs the therapeutic agent preferentially to diseased cells is a routine strategy to minimize off-target side effect of the therapeutic agent. Additionally, one of ordinary skill in the art would also have a reasonable expectation of success conjugating the conjugating the FX11 of Le to the TLR9-targeting CPG ODN-STAT3 siRNA molecule of Yu with the net result being CpG-ODN that is covalently linked to both the STAT3 siRNA of Yu and the FX11 of Li that is administered in methods of treating lymphoma because: 1) Yu teaches that the CpG ODN-STAT3 siRNA conjugate of Yu is useful for treating lymphoma, 2) Le teaches that FX11 is also useful for treating lymphoma and 3) combining two compositions each of which is taught by the prior art to form a third composition to be used for the very same purpose is a prima facie obvious combination (see MPEP § 2144.06(I)).
Claim(s) 1-8, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 and is/are rejected under 35 U.S.C. 103 as being unpatentable over Yu (Yu, et al., WO 2008/094254 A2; Published 8/7/2008; Priority to 1/26/2007 via US 60/897,495) as evidenced by Nechaev (Nechaev, et al., J. Controlled Release; 2013 170:307) as applied to claims 1-3, 5, 12, 21-22, 24, 40, 45-46, 59, 62, 71 and 75-77 and above and in further view of Yasuda (Yasuda, et al., J. Immunol. 2009; 183(5): 3109).
The teachings of Yu are discussed above. In addition, Yu teaches that the CpG oligonucleotides of Yu are oligonucleotides containing a CpG motif that are between 2 and 100 bp in length (Yu, ¶ 0036).
Yu does not teach that the TLR9-targeting CpG polynucleotide of Yu is dsDNA with each strand being 30 and 50 nucleotides in length.
Yasuda teaches that mammalian DNA (which is dsDNA) can be an effective TLR9 ligand, with the strongest TLR9 activation seen with dsDNA fragments containing optimal CpG motifs (purine-purine-CpG-pyramiding-pyrimidine) (Yasuda, Abstract).
It would be prima facie obvious to one of ordinary skill in the art to use the substitute the use the dsDNA comprising the optimal CpG motifs as taught by Yasuda as the TLR9 directing component in the multifunctional molecules of Yu. One of ordinary skill in the art would be motivated to do this in order to make a dsDNA-based TLR9 targeting polynucleotide that is equivalent to the CpG-ODN TLR9 targeting polynucleotides taught by Yu. One of ordinary skill in the art would have a reasonable expectation of success using the dsDNA comprising the optimal CpG motifs as taught by Yasuda as the TLR9 directing component of the multifunctional molecules of Yu because substituting equivalents known for the same purpose is a prima facie obvious combination. This additionally reads on claims 4 and 6.
It would be prima facie obvious to one of ordinary skill in the art to start with the TLR9-targeting, CpG comprising dsDNA taught by Yoshida and the nucleic acid targeting module length of 2 to 100 bp taught by Yu and arrive at a TLR9-targeting, CpG-comprising dsDNA that is 30 to 50 bp in length through routine experimentation. One of ordinary skill in the art would be motivated to do this in order to optimize the TLR9 binding properties of the dsDNA of Yoshida. One of ordinary skill in the art would have a reasonable expectation of success starting with the TLR9-targeting, CpG comprising dsDNA taught by Yoshida and the nucleic acid targeting module length of 2 to 100 bp taught by Yu and arriving at a TLR9-targeting, CpG-comprising dsDNA that is 30 to 50 bp in length through routine experimentation because: 1) Yoshida teaches CpG-comprising dsDNA as a TLR9 targeting nucleic acid ligand, 2) Yu teaches TLR9-targeting, CpG comprising nucleic acids with lengths between 2 and 100 bp and 3) starting with ranges of nucleotide lengths disclosed in the prior art and arriving at optimized nucleotide lengths within their respective disclosed range is well within the purview of one of ordinary skill in the art.
Additionally, in the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990) (The prior art taught carbon monoxide concentrations of "about 1-5%" while the claim was limited to "more than 5%." The court held that "about 1-5%" allowed for concentrations slightly above 5% thus the ranges overlapped.); In re Geisler, 116 F.3d 1465, 1469-71, 43 USPQ2d 1362, 1365-66 (Fed. Cir. 1997) (Claim reciting thickness of a protective layer as falling within a range of "50 to 100 Angstroms" considered prima facie obvious in view of prior art reference teaching that "for suitable protection, the thickness of the protective layer should be not less than about 10 nm [i.e., 100 Angstroms]." The court stated that "by stating that ‘suitable protection’ is provided if the protective layer is ‘about’ 100 Angstroms thick, [the prior art reference] directly teaches the use of a thickness within [applicant’s] claimed range."). See also In re Bergen, 120 F.2d 329, 332, 49 USPQ 749, 751-52 (CCPA 1941) (The court found that the overlapping endpoint of the prior art and claimed range was sufficient to support an obviousness rejection, particularly when there was no showing of criticality of the claimed range). Please note that this modification additionally reads on claims 7-8.
Allowable Subject Matter
Claim 9 is objected to as being dependent upon a rejected base claim, but would be allowable if rewritten in independent form including all of the limitations of the base
claim and any intervening claims.
The following is a statement of reasons for the indication of allowable subject matter: a multidata base sequence was performed for all of instant SEQ ID NOs: 40-42. The next nearest prior art for all sequences was SEQ ID NO: 19 of Krishnan (Krishnan, et al., WO 2015033237; Published 5/12/2015). Krishnan teaches on the subject of nucleic acid sensors for cAMP comprising a reporter domain and target recognition domain (Krishnan, Abstract). Krishnan teaches that modular RNA aptamer sensors comprise three domains: target recognition domain, communication domain and reporter domain (Krishnan, p 1, lines 25-34). Krishnan teaches that the target recognition domain binds to the target to be detected with the communication module transferring the information from the target recognition domain to the reporter domain, such that whenever the recognition domain binds a target, the reporter domain will give a fluorescence signal (Krishna, p 1, lines 25-34). All of the sequence reading on instant SEQ ID NOs: 40-42 are associated with labeled complementary DNA having Krishan’s SEQ ID NO: 19, which is labeled complementary nucleic acid that hybridizes with a 3’ overhang of Krishnan’s SEQ ID NO: 18, which acts as the nucleic acid sensor (Krishna, claims 13 and 15). While the Krishnan reference does discuss targeting moieties that are nucleic acids, one of ordinary skill in the art would be unlikely to start with SEQ ID NO: 19 of Krishan and arrive at the instant claimed invention because SEQ ID NO: 19 of Krishnan is used as a label and not as a targeting module as required by the instant claims.
Conclusion
Claims 1-8, 12, 14-22, 24, 40, 44-46, 59, 62, 65 ,71, 75-77 and 82 are rejected.
Claim 9 is objected to.
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Sydney Van Druff whose telephone number is (571)272-2085. The examiner can normally be reached 10 am - 6 pm.
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://patentcente