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 .
Status of the Claims
Claims 1-20 are currently pending and under examination.
Priority
Acknowledgment is made of applicant’s claim for foreign priority under 35 U.S.C. 119 (a)-(d). The certified copy has been filed in parent Application No. CN2023101249665, and CN2023101331462 filed on 9 February 2023; CN2023101530678 and CN2023101331477, filed on 20 February 2023. As such, the effective filing date of the claims is 9 and 20 February 2023.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 November 2023. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
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.
Claims 1, 2, 13 and 15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while describing administration of compound C1632, provides limited support for therapeutic use and does not reasonably enable the full scope of the claimed invention. The specification provides insufficient evidence or working examples demonstrating treatment or prevention of specific claimed diseases such as Alzheimer’s disease, diabetes, osteoarthritis and atherosclerosis. While the specification provides certain experimental data relating to fibrosis -related and vascular calcification models, the disclosure does not establish that administration of c1632 is effective for each of the broad disease categories recited in the claims, nor does the specification establish efficacy across the full scope of patient populations encompassed by the claims. In particular, the specification does not identify a specific patient population for prevention therapy or provide guidance demonstrating prophylactic administration sufficient to prevent senescence and/or senescence -related diseases. The specification does not establish that compound C1632 belongs to a recognized class of compounds previously known in the art to successfully prevent and treat the recited diseases.
The instant claims are drawn to a method of treating or preventing senescence and/or senescence-related diseases in a subject comprising administering a compound of Formula (l). The specification fails to provide information that would allow the one skilled in the art to practice therapeutically preventing senescence and/or senescence-related diseases.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG V. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by In re Wands, 8 USPQ2d 1400 (CAFC1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
the nature of the invention
the state of the prior art
the predictability of the art
the amount of direction or guidance provided
the presence or absence of working examples
the breadth of the claims
the quantity of experimentation necessary
the relative skill of those in the art
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
I. The nature of the invention - is a method of treating and/or preventing senescence and/or senescence-related diseases in a subject comprising administering a compound of Formula (l) C1632.
II. The state of the art - the pharmacological art requires the screening of potential drug candidates in vitro and in vivo to determine if the drug candidates exhibit the desired pharmacological activities.
In order to treat a disease: one would need to precisely identify what the disease is, identify what biological target is connected with the disease, demonstrate that the drug candidate in some way modulates the normal processes of the biological target, and demonstrate that a patient benefited from such modification without detrimental side effects. Typically, this process includes in vitro laboratory screening, preclinical in vivo screening, and three phases of clinical trials. Once this arduous process has been successfully completed by a drug candidate, subsequent drug candidates will benefit from the established proof of concept. The subsequent drug candidates must demonstrate a substantial correlation between their biological activity and that of the known drug candidate.
In order to prevent a disease: one would need to precisely identify those subjects likely to acquire such a disease, administer Applicant's claimed invention, and demonstrate that the patient did not develop the disease as a result of the administration of the claim invention.
In the instant case, the state of the art did not establish that administration c1632 could be used predictably to prevent senescence or to prevent senescence-related disease. The recited diseases are not a single, predictable therapeutic class, but instead are managed using materially different therapeutic approaches. For instance, atherosclerosis is managed primarily with statin-based lipid therapy (Vaughan et al. JACC 2000, 35(1), 1-10, p. 1 title, abstract); Alzheimer’s disease is treated with cholinesterase inhibitors (Raina et al Annals of internal Medicine 2008 148(5), 379-397, p. 379, title, Purpose); Osteoarthritis is managed with topical or oral NSAIDS and intraarticular glucocorticoid injections (Kolasinski et al. Arthritis Care & Research 2020, 72(2), 149-162, results p. 149); and idiopathic pulmonary fibrosis is treated with antifibrotic agents such as nintedanib and pirfenidone (Raghu et al. AJRCCM 2022 205(9), e18-e47 methods p. e18). Therefore, success of c1632 in one disease setting would not have reasonably predicted success across the others.
III. The predictability or unpredictability of the art - The relevant inquiry is not whether the pharmaceutical is unpredictable art, but whether one of ordinary skill in the art could have extrapolated the disclosed or know results to the full scope of the claimed invention. The MPEP explains that the "predictability or lack thereof" in the art refers to the ability of one skilled in the art to extrapolate the disclosed or known results to the claimed invention, and that the amount of guidance needed for enablement is inversely related to the predictability of the art. In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970). MPEP 2164.03. In the instant case, the claimed methods encompass prevention or treatment of multiple senescence-related disease using C1632. Because the claimed diseases do not represent a single predictable therapeutic setting, success of C1632 in one disease context would not have reasonably permitted one of ordinary skill in the art to extrapolate that same result across the full scope of the claimed disease.
IV. The amount of direction or guidance presented - The instant specification provides an explanation of the biological activity of senescence-related diseases, which are defined as any functional changes in the organism, or any tissues, organs, or cells thereof, occurring with a decline in reproductive function after the period of maximum reproductive function, change is aging-related. Senescence-related diseases refer to any diseases, disorders, degenerations, tissue loss, or other unhealthy or abnormal conditions caused by or associated with senescence on page 2, and discusses the implication of C1632 in the treatment of senescence-related diseases. There is no direction or guidance provided that supports a use of C1632 as a drug for preventing senescence-related diseases.
The amount of guidance or direction to enable the invention is inversely related to the amount of knowledge in the state of the art as well as the predictability in the art. MPEP § 2164.03 (quoting In re Fisher, 427 F.2d 833, 839, 166 USPQ 18 24 (CCPA 1970)). As identified supra, the pharmaceutical art is recognized as unpredictable.
Thus, in order to support a claim for preventing senescence-related diseases and treating the full scope of senescence-related diseases a vast amount of evidence is required because such a claim is not supported by the prior art or the instant specification.
V. The presence or absence of working examples - The assays in the specification demonstrate that the instant compound were tested for their ability to (I)significantly inhibit cellular senescence, extend lifespans of mice, inhibit lung senescence, relieve the immunosuppressive microenvironment during senescence, promotes immune clearance of senescent cells, and treats senescence-related diseases; (2) significantly inhibit the progression of liver fibrosis, have strong safety profile and anti- liver fibrosis effect, and can be used as a candidate drug for the treatment of liver fibrosis; (3) significantly inhibit the progression of idiopathic pulmonary fibrosis, reduce fibroblast proliferation and collagen synthesis during idiopathic pulmonary fibrosis, inhibit the activity of inflammatory infiltration of immune cells, protect alveolar architecture and reduce the elevated lung density during idiopathic pulmonary fibrosis, ameliorate lung density and ventilation; (4) significantly inhibit the progression of kidney fibrosis of mice caused by chronic kidney disease, ameliorate the weight loss of mice caused by chronic kidney disease and reduces the mortality of mice caused by chronic kidney disease; (5) ameliorate aortic vascular calcification and vascular compliance in mice. Those examples are limited to certain specific experimental models and do not enable the full scope of the claimed invention. The specification does not provide working examples for several expressly claimed disease, including, osteoarthritis, atherosclerosis, diabetes, autoimmune diseases and Alzheimer’s disease, nor does it provide working examples demonstrating prophylactic prevention across the full scope of the claimed senescence-related diseases.
VI. The breadth of the claims – The claim is broad, encompassing many different diseases, atherosclerosis, vascular calcification, diabetes, autoimmune diseases, osteoarthritis, Alzheimer's disease, or tissue and organ fibrosis, all have different causes, affect different physiological processes, and are treated with different agents. “Age-related disorders” encompasses many conditions. Claims are incommensurate in scope with the disclosure because a fair reading of the specification fails to support a finding that the compounds of instant formula (l) may prevent senescence-related diseases in a patient.
VII. The quantity of experimentation necessary - generally speaking, the amount of experimentation to transform a molecule into medicine is vast and the success thereof is low. Recent statistics indicate that the attrition rates during drug development remain high. Schafer et al. makes clear that there are many steps necessary to promote a new molecular entity toward its clinical use, any one of which is cumbersome (Schafer et al. Drug Discovery Today 2008, 13 (21/22), 913-916).
For instance, Schafer et al. discloses: "proof of concept trials have failed when the decision to enter clinical development was based on preclinical experiments using the wrong compound, the wrong experimental model, or the wrong endpoint." It can be gleaned from this article that a plethora of experimentation is needed to identify the lead compound (i.e. one among many in a Markush-type claim), to establish which preclinical tests are predictive of clinical success, and to establish which diseases are the best to target for each lead compound.
There is generally a vast amount of experimentation to take a drug from bench to the clinic. Horig et al. suggest that successful drug development requires satisfying a matrix of domains from the disease relevance and target druggability to the feasibility of drug delivery and demonstration of a favorable benefit-risk profile. Meeting these requirements ensures a drug label that gains physician and patient acceptance. The amount of experimentation required to enable a pharmaceutical drug is extensive (Horig et al. Journal of Translational Medicine 2004, 2, 44).
VIII. The level of skill in the art - the level of ordinary skill in the art may be found by inquiring into: (1) the type of problems encountered in the art; (2) prior art solutions to those problems; (3) the rapidity with which innovations are made; (4) the sophistication of the technology; and (5) the education level of active workers in the field. Custom Accessories, Inc. v. Jeffrey-Allan Industries, Inc., 807 F.2d 855, 962 (Fed. Cir. 1986). All of those factors may not be present in every case, and one or more of them may predominate. Envtl. Designs, Ltd. V. Union Oil Co., 713 F.2d 693, 696 (Fed. Cir. 1983).
Based on the typical education level of the active workers in the field of pharmaceuticals and/or medicine, as well as the high degree of sophistication required to solve problems encountered in the art, a person of ordinary skill in the art would have at least a college degree in a field related to medicine and/or the pharmaceutical art and at least four years of work experience, i.e. a masters or doctorate level scientist/clinician.
Therefore, claims 1, 2, 13 and 15 are rejected because the Wands factors suggest a conclusion that the skilled artisan would not be able to make and use the instant invention without undue experimentation, although the level of skill for an ordinary person in the art is high. That is, the breadth of the claims, the unpredictability of the art, the lack of guidance or direction from the disclosure, the lack of any working examples, and the amount of experimentation needed, together illustrate that a person having ordinary skill in the art would not be able to prevent senescence and/or senescence-related diseases.
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.
Claims 1-20 are rejected under 35 U.S.C. 103 as being unpatentable over Roos et al (ACS chemical biology, 2016 11(10), 2773-2781; hereinafter “Roos”) in view of Lekka et al. (Nature Communications, 2022, 13(1), 7940-7940; hereinafter “Lekka”) and Wang et al. (Biomolecules 2022, 12, 1070; hereinafter “Wang”) and further in view of Liang et al. (J Mol. Med. 2016 94:655–665; hereinafter “Liang”) and Li et al. (Int. J. of Mol. Med. 2019, 44: 1619-1628; hereinafter “Li”).
Roos teaches compound C1632, namely N-methyl-N-[3-(3-methyl[1,2,4]triazolo[4,3-b]pyridazin-6-yl)phenyl]acetamide, as a small-molecule inhibitor of Lin28 (See e.g. p. 2773, Abstract). Roos teaches that Lin28 binds to conserved sites in let-7 precursor RNAs and prevents maturation of let-7 microRNAs by inhibiting Drosha and Dicer-mediated processing(See e.g. p. 2773, col. 1, line 18). Roos further teaches that C1632 blocks the Lin28/let-7 interaction, rescues let-7 processing and function in Lin28-expressing cells, induces differentiation of mouse embryonic stem cells, and reduces tumor-sphere formation in 22Rv1 and Huh7 cells(See e.g. p. 2773, Abstract, p. 2774, Fig. 1; p. 2775 Fig. 3). Roos therefore teaches a known compound, C1632, that inhibits Lin28 and restores let-7 activity.
Roos, however, does not explicitly teach treating or preventing senescence-related diseases, including tissue and organ fibrosis.
Lekka teaches that C1632 is a drug-like Lin28 inhibitor and that the Lin28/let-7 axis regulates metabolic pathways in liver cells(See e. g. p. 1 Abstract, line 6). Lekka that C1632 inhibits Lin28 binding to let-7 precursors, has suitability for in vivo use, and increases hepatic let-7a, let-7b, let-7c, and let-7g after administration to mice teaches (See e.g. p. 2, col. 2 line 15). Lekka further teaches that C1632-mediated Lin28 inhibition activates ketogenesis, suppresses lipogenesis, restores lipid homeostasis, and protects against lipid accumulation in cellular and mouse models of hepatic steatosis/non-alcoholic fatty liver disease(See e.g. p. 7, col.1 line5). Lekka therefore teaches that C1632-mediated Lin28/let-7 modulation has in vivo biological activity and therapeutic utility in a disease model. This teaching reads on claims 1–12 because the claims broadly require use of C1632 or a Formula (I) compound for treating or preventing senescence-related diseases, and further supports claims 13–20 because Lekka teaches actual in vivo administration of C1632.
Wang teaches that abnormal regulation and expression of let-7 are closely related to aging and aging-related diseases (See e.g. p. 1 Abstract and introduction). Wang teaches that let-7 is elevated in aging tissues and participates in multiple pathways regulating aging, including tissue stem cell function, body metabolism, immune function, and aging-related diseases (See e.g. p. 1 Abstract and introduction). Wang further teaches that let-7 plays roles in different tissue aging and aging-related diseases, including neurological aging and Alzheimer’s disease(See e.g. p. 5; section 3 “Let-7 and Lifespan” p. 6 section 3.1.1 “Let-7 and the Nervous System.”). Wang therefore supplies the aging-related disease context for the Lin28/let-7 pathway modulation taught by Roos and Lekka. This teaching reads on claims 1–12 to the extent the claims recite treating or preventing senescence, senescence-related disease, or aging-related disease.
Liang teaches that idiopathic pulmonary fibrosis is a chronic, progressive, and highly lethal fibrotic lung disease(See e. g. p. 655 Abstract; Introduction). Liang further that Lin28B is increased in lungs of mice with experimental lung fibrosis and in idiopathic pulmonary fibrosis teaches (See e. g. p. 658 Col.1 Results section “The Lin28B/let-7d axis is manifest in pulmonary fibrosis”). Liang teaches that Lin28B causes epithelial-mesenchymal transition and dysregulation of EMT-related proteins by inhibiting let-7d, thereby contributing to the progression of idiopathic pulmonary fibrosis(See e.g. p. 658 Results section “Lin28B promotes EMT via suppression of let-7d). Conversely, Liang teaches that inhibition of Lin28B ameliorates TGF-β1-induced EMT and collagen formation, and that miR-26a enhances let-7d expression through regulation of Lin28B. Liang therefore teaches that inhibition of Lin28B and restoration of let-7 activity are useful in fibrotic disease, including pulmonary fibrosis. This teaching reads on claims 6–12 to the extent the claims recite tissue and organ fibrosis, including pulmonary fibrosis.
Li teaches that miR-379-5p suppresses renal fibrosis by regulating the LIN28B/let-7 axis in diabetic nephropathy(See e. g. p. 1619, Abstract). Li teaches that miR-379-5p expression was downregulated and LIN28B expression was upregulated in mouse mesangial cells treated with high glucose and in glomeruli of db/db mice(See e.g. p. 1626, col. 1 line 16). Li teaches that miR-379-5p mimics and agomir suppressed LIN28B expression in vitro and in vivo, respectively, and that let-7b, downstream of LIN28B, was upregulated when miR-379-5p expression was increased further (See e.g. p. 1626, col. 1 line 20). Li teaches that overexpression of miR-379-5p alleviated mouse mesangial cell proliferation and collagen protein accumulation, suggesting suppression of renal fibrosis by regulating the LIN28B/let-7 axis in diabetic nephropathy(See e.g. p. 1626, col. 2 line 3). Li therefore provides additional disease-specific evidence that suppression of LIN28B and restoration of let-7 activity reduce organ fibrosis, particularly renal fibrosis. This teaching reads on claims 6–12 to the extent the claims recite tissue and organ fibrosis, including kidney or renal fibrosis.
With respect to CD45, CD68, and CD3, these were known immunohistochemical markers used to identify immune-cell populations in tissue samples, particularly in studies of inflammation, fibrosis, and cancer. CD45 is a general leukocyte marker, CD3 identifies T cells, and CD68 identifies macrophages/monocytes. These markers are conventional tools for evaluating immune-cell infiltration and inflammatory microenvironments. Accordingly, to the extent claims 1–12 recite detecting, reducing, or analyzing immune-cell infiltration or inflammatory-cell populations in senescence-related disease models, the use of CD45, CD68, and CD3 would have been within the ordinary skill in the art.
Regarding claims 13–20, the claims further define the known compound C1632 into pharmaceutical compositions, pharmaceutically acceptable excipients, dosage forms, routes of administration, or therapeutic formulations. The use of pharmaceutically acceptable carriers, excipients, diluents, and conventional dosage forms for administering a known therapeutic compound was well known and routine in the pharmaceutical art. A person of ordinary skill in the art would have known how to formulate an active compound such as C1632 with pharmaceutically acceptable excipients into conventional dosage forms suitable for administration, including oral, parenteral, injectable, or other standard routes. Therefore, the formulation, excipient, dosage-form, and administration-route limitations of claims 13–20 would have been obvious once the use of C1632 for the claimed therapeutic purpose was suggested by the combined teachings of Roos, Lekka, Wang, Liang, and Li.
It would have been obvious to one of ordinary skill in the art before the effective filing date of the invention to use the C1632 compound taught by Roos, as further characterized by Lekka, for treating or preventing senescence-related diseases and fibrotic diseases suggested by Wang, Liang, and Li. Roos teaches the specific compound C1632 and its ability to inhibit Lin28 and restore let-7 activity. Lekka confirms that C1632-mediated Lin28 inhibition is active in vivo and produces beneficial effects in a disease model. Wang teaches that let-7 is involved in aging, senescence, and aging-related diseases. Liang teaches that inhibition of Lin28B and restoration of let-7d reduces EMT, collagen formation, and fibrogenesis in pulmonary fibrosis. Li teaches that suppression of LIN28B and upregulation of let-7 reduces renal fibrosis in diabetic nephropathy.
Therefore, one of ordinary skill in the art would have been motivated to apply the C1632-mediated Lin28/let-7 pathway modulation taught by Roos and Lekka to senescence-related diseases and fibrotic conditions, including pulmonary and renal fibrosis, because Liang and Li teach that suppression of Lin28/LIN28B and restoration of let-7 activity reduce fibrotic disease processes. One of ordinary skill in the art would have had a reasonable expectation of success because the references collectively identify the same biological axis, namely Lin28/LIN28B inhibition and let-7 restoration, as relevant to aging-related disease biology and fibrosis, and Roos and Lekka provide C1632 as a known small-molecule means of modulating that pathway.
Accordingly, claims 1–20 are obvious over the cited combination.
Conclusion
No claims are allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to GENBIN SHI whose telephone number is (571)272-8796. The examiner can normally be reached Mon-Fri, 8:00am-5pm.
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, Amy Clark can be reached at (571) 272-1310. 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.
/G.S./ Examiner, Art Unit 1628 /AMY L CLARK/Supervisory Patent Examiner, Art Unit 1628
Prosecution Insights