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 .
Claims 3 and 9 have undergone amendments. Claims 6-8 have been cancelled. Claims 1, 2, 10, 16, 17, 20, and 22 are withdrawn. Claims 3-5, 9, 12, and 15, submitted on 22 January 2026 represent all claims currently under consideration.
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.
Election/Restrictions
Claim 3 is allowable. The restriction requirement between groups , as set forth in the Office action mailed on 14 February 2025 , has been reconsidered in view of the allowability of claims to the elected invention pursuant to MPEP § 821.04(a). The restriction requirement is hereby withdrawn as to any claim that requires all the limitations of an allowable claim. Specifically, the restriction requirement of 14 February 2025 is partially withdrawn. Claims 16, 17, 20, and 22 , directed to methods of use of compounds of general formula (A)K-L1-Q is no longer withdrawn from consideration because the claims require all the limitations of an allowable claim. However, Claims 1, 2, and 10, directed to Compounds of Formula I, II, III, IV, V, VI, VII, VIII, IX, and X remain withdrawn from consideration because these compounds do not require all the limitations of an allowable claim.
In view of the above noted withdrawal of the restriction requirement, applicant is advised that if any claim presented in a divisional application is anticipated by, or includes all the limitations of, a claim that is allowable in the present application, such claim may be subject to provisional statutory and/or nonstatutory double patenting rejections over the claims of the instant application.
Once a restriction requirement is withdrawn, the provisions of 35 U.S.C. 121 are no longer applicable. See In re Ziegler, 443 F.2d 1211, 1215, 170 USPQ 129, 131-32 (CCPA 1971). See also MPEP § 804.01.
Claims 3-5, 9, 12, 15-17, 20, and 22, submitted on 22 January 2026 represent all claims currently under consideration.
Response to Amendment
The objection to Claim 6 is withdrawn. Applicant has cancelled the claim, rendering the objection moot.
Each of the 35 U.S.C. § 102 rejections of the previous Office Action are withdrawn. Applicant has cancelled Claims 6-8, and amended Claim 1 to incorporate the matter from Claim 9 which was not rejected in the prior Office Action.
Claim Objections
Claim 20 is objected to because of the following informalities: There is a semi-colon (;) following Meiner’s syndrome in the Markush list of conditions, and the Examiner believes it should be a comma. Appropriate correction is required.
Claim 20 is objected to because of the following informalities: “Multiple sclerosis” is listed twice in the Markush list of conditions to be treated. Appropriate correction is required.
Claim Rejections - 35 USC § 112(a)- NEW GROUNDS OF REJECTION
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 16 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 the treatment of conditions associated with dysregulated histone deacetylases, bromodomains, MDM2, p53, and tyrosine kinases such as Her2, MAPK, mTOR kinases, VEGFR, PDGFR, and RAF kinases, it does not reasonably provide enablement for the treatment of all conditions associated with dysregulated proteins. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating a disease in a subject wherein dysregulated protein is responsible for said disease, comprising administering a composition comprising a compound of Claim 3. The compounds of Claim 3 are bifunctional protein degraders, wherein the targeting moiety is selected from immunosuppressants, antibiotic inhibitor of bacterial DNA synthesis, a histone deacetylase inhibitor, bromodomain inhibitor, MDM2/p53 inhibitor , tyrosine kinase inhibitors, MAPK inhibitor, mTOR inhibitor , and inhibitor of VEGFR, PDGFR, and RAF kinases. Thus, the claims are directed to a method which can be used to treat any disease caused by dysregulated protein using the compounds which are conjugated to the degron compound of Claim 3.
The state of the prior art and the predictability or unpredictability of the art:
The prior art demonstrates that conditions which are regulated by proteins which are targeted by these compounds can be treated predictably, such as various cancers wherein overexpression or overactivity of these proteins is known. However, not all dysregulated proteins involved in disease are able to be targeted by the inhibitors or compounds which are attached to the degron of Claim 3. For example, Huntington’s disease is caused by dysregulation of the huntingtin protein. Ferguson (Journal of Central Nervous System Disease, 2022 May 21) provides a review of current and possible therapeutic options to treat Huntington’s disease. Huntington’s disease (HD) is an autosomal neurodegenerative disease caused by an excessive number of CAG trinucleotide repeats within the huntingtin gene. There are many new HD therapeutics currently undergoing clinical trials that target the disease at its origin by lowering the levels of mutant huntingtin protein (mHTT). Potential therapies include zinc-finger protein therapies, transcription activator-like effector nuclease therapies, and CRISPR/Cas therapies (Abstract). Table 1 lists the most commonly used medications for the treatment of Huntington’s disease, and includes chorea medications such as tetrabenazine and deutetrabenzanine, antipsychotics such as olanzapine and risperidone, SSRIs such as citalopram, fluoxetine, and sertraline, and mood stabilizes such as lamotrigine and carbamazepine. Table 2 lists potential future treatments for Huntington’s disease, and includes RNA targeting therapies, RNAi therapies, small molecules such as branaplam, PTC518, pridopidine, laquinimod, fenofirbrate, neflamapimod, nilotinib, SRX246, vareniclin, SAGE-718, and PBT2 DNA targeting therapies that target zinc protein fingers, and antibody therapies. Other conditions such as Alzheimer’s disease are caused by dysregulation of the tau protein and formation of aggregates. Zheng (International Journal of Molecular Sciences, 2024, 25, 4969) provides a review of the tau protein and its involvement in Alzheimer’s disease. Tau protein misfolding and aggregation are pathological hallmarks of Alzheimer’s disease and over twenty neurodegenerative disorders. There are two types of tau aggregates in the brain: soluble aggregates (oligomers and protofibrils) and insoluble filaments (fibrils). In its native state, tau is highly soluble and heat stable, and does not form fibrils by itself, not even when hyperphosphorylated. Two breakthroughs have provided new insights into tau aggregation mechanisms: tau undergoes liquid-liquid phase separation in vitro and inside cells, and there are diverse fibrillar tau conformations associated with different neurodegenerative disorders (Abstract). The common features of many neurodegenerative disorders are the misfolded aggregates of one or a few critical proteins. They are also called protein misfolding disorders or protein conformational diseases. Misfolded proteins form inclusions called amyloids, which appear as nanosized fibrils/filaments with extensive cross-β structures. AD is characterized by two protein lesions: senile plaques containing beta-amyloid (Aβ) peptide and neurofibrillary tangles (NFTs) containing tau. Tau inclusions have been further identified in dozens of neurodegenerative disorders, more than any other amyloid protein. In most tauopathies, the majority of tau inclusions are found within neurons. Because pathological tau is hyperphosphorylated, there have been clinical trials with kinase inhibitors against GSK3β and Fyn. An alternative approach is to enhance O-GlcNAc glycosylation to reduce phosphorylation, using inhibitors of O-GlcNAcase. However, these enzymes are promiscuous not specific to tau pathways, and their inhibition may cause potential side effects. Another class of small-molecule drugs being clinically tested is based on the “molecular chaperone” idea, trying to prevent or modulate tau misfolding pathways to reduce toxicity, including methylene blue, HMTM (a methylene blue derivative), CI-3024, and OLX-07010. In terms of biological drugs, two antisense oligonucleotides against MAPT have entered clinical trials, aiming to reduce tau expression via ribonuclease H-dependent m-RNA degradation. Such therapies will likely also reduce physiological tau expression in non-degenerating brain regions (5. Tau Therapeutics). Thus, these diseases are caused by dysregulation of tau and Aβ proteins, which causes aggregation and neuronal cell death, among other cell types which may be affected.
The relative skill of those in the art:
The artisan would generally have a medical degree and further specialized training in the treatment and management of neurodegenerative diseases; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat all forms of disease caused by dysregulated protein as the compounds claimed do not contain moieties which are known in the art to effect proteins associated with conditions such as Alzheimer’s (tau protein) or Huntington’s Disease (huntingtin protein).
The amount of direction or guidance presented and the presence or absence of working examples:
Example 9 (Page 382) of the specification provides data demonstrating that dihydrofolate reductase, estrogen receptor α, HDAC6, and BRD4 are capable of being degraded using compounds of the invention. The specification does not provide any data or examples demonstrating the treatment of all diseases caused by dysregulated protein; for example, the specification does not demonstrate that compounds of the invention are capable of binding proteins such as aggregated tau or huntingtin protein, nor does it demonstrate that these compounds are capable of crossing the blood-brain barrier, which would be necessary for the treatment of these neurological disorders caused by dysregulated proteins. Thus, the specification does not provide examples for the treatment of all conditions caused by dysregulated proteins.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of targeting moieties for every possible protein that can be dysregulated in the pathology of disease, and the high unpredictability of the art as evidenced therein, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim 20 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 many of the claimed autoimmune disorders, does not reasonably provide enablement for the treatment specifically of pernicious anemia. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. Consideration of the relevant factors sufficient to establish a prima facie case for lack of enablement is set forth below:
The nature of the invention and breadth of the claims:
The claims are directed towards a method of treating an autoimmune disease in a subject wherein dysregulated protein is responsible for said disease, comprising administering a composition comprising a compound of Claim 3. The compounds of Claim 3 are bifunctional protein degraders, wherein the targeting moiety is selected from immunosuppressants, inhibitor of dihydrofolate reductase, a histone deacetylase inhibitor, bromodomain inhibitor, MDM2/p53 inhibitor , tyrosine kinase inhibitors, MAPK inhibitor, mTOR inhibitor , and inhibitor of VEGFR, PDGFR, and RAF kinases. Thus, the claims are directed to a method which can be used to the claimed autoimmune disorders caused by dysregulated protein activity using the compounds which are conjugated to the degron compound of Claim 3.
The state of the prior art and the predictability or unpredictability of the art:
The compounds of Claim 3 are linked with immunosuppressants, which enable the treatment of conditions such as multiple sclerosis, lupus, transplantation rejection, rheumatoid arthritis, and other conditions which are known in the art to be capable to treatment using immunosuppressants. However, there is no demonstration in the prior art that immunosuppressants can be used to treat pernicious anemia. Ammouri (European Medical Journal Reviews, 2020; 1: 71-80) provides an overview of pernicious anemia and its current treatment paradigms. Pernicious anemia is an autoimmune disorder, and is the most common cause of cobalamin deficiency anemia worldwide. This disease is a macrocytic anemia caused by a vitamin B12 deficiency, which is the result of deficiency of intrinsic factor, a protein that binds to dietary vitamin B12 and promotes its transport to the terminal ileum for absorption (Abstract). Intrinsic factor is a glycoprotein that binds to cobalamin and enables its absorption within the terminal ileum. The deficiency of intrinsic factor is a consequence of atrophic gastritis, which results in the destruction of oxyntic mucosa and thus the loss of parietal cells, which normally produce hydrochloric acid as well as intrinsic factor. Acid loss leads to iron deficiency anemia that precedes cobalamin-deficient pernicious anemia by many years (Introduction). The clinical management of patients with pernicious anemia has two different aspects: the treatment of cobalamin deficiency and the monitoring of iron deficiency onset. Pernicious anemia is caused by inadequate secretion of gastric intrinsic factor, which is necessary for vitamin B12 absorption and thus cannot be treated with oral vitamin B12 supplements. The therapeutic recommendations for pernicious anemia are divergent. Vitamin B12 must be administered parenterally and patients generally receive an intramuscular injection of 1,000 µg of B12 every day or every other day during the first week of treatment. The next month, they receive injections every week, subsequently followed by monthly injections. Pernicious anemia requires lifelong treatment and the percentage of vitamin B12 absorption improves with supplementation, but symptoms of vitamin B12 deficiency may be improved after just a few days of medical treatment (Treatment). Thus, the current treatment paradigm indicates that pernicious anemia is the result of the loss of the function of a protein (intrinsic factor), and the only known current treatment is injection or oral administration of vitamin B12. The current state of therapy for pernicious anemia does not indicate that targeted degradation of a protein would result in an effective, predictable method of treating this condition.
The relative skill of those in the art:
The artisan would generally have a medical degree and training in rheumatology, hematology or immunology; however, their high level of training and knowledge would not be sufficient to overcome the lack of understanding of how to use the claimed compounds to treat pernicious anemia, as the only recognized treatment for pernicious anemia is injections of vitamin B12, with no indication that degrading any protein involved in the absorption of vitamin B12 would provide any benefit for the treatment of pernicious anemia.
The amount of direction or guidance presented and the presence or absence of working examples:
Example 9 (Page 382) of the specification provides data demonstrating that dihydrofolate reductase, estrogen receptor α, HDAC6, and BRD4 are capable of being degraded using compounds of the invention. The specification does not provide any data or examples demonstrating the treatment of pernicious anemia as there is no data provided demonstrating that compounds of the invention can result in improved absorption of vitamin B12.
The quantity of experimentation necessary:
Considering the state of the art as described above, in particular with regards to the lack of current evidence in the art of treating pernicious anemia that degrading a target protein would result in improved B12 absorption, and the lack of guidance provided in the specification, one of ordinary skill in the art would be burdened with undue experimentation to practice the invention commensurate with the scope of the claims.
Claim Rejections - 35 USC § 112(b)- NEW GROUNDS OF REJECTION
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 17 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. Regarding claim 17, the phrase "including Ewing’s sarcoma, hemangiosarcoma, Kaposi’s sarcoma, liposarcoma, myosarcomas, peripheral neuroepithelioma, synovial sarcoma, gliomas, astrocytoma, oligodendrogliomas, ependymomas, glioblastoma, neuroblastomas, ganglioneuromas, gangliogliomas, medulloblastomas, pineal cell tumors, meningiomas, meningeal sarcomas, neurofibromas, Schwannomas, testicular cancer, thyroid cancer, astrocytoma, Hodgkin’s disease, Wilms’ tumor, and teratocarcinomas" renders the claim indefinite because it is unclear whether the limitations following the phrase are part of the claimed invention. See MPEP § 2173.05(d).
Claim 20 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 20 is indefinite because of the limitation “and other autoimmune diseases or disorders”. The specification does not define what encompasses “other autoimmune diseases or disorders”, causing the metes and bounds of the claim to be undefined, and therefore, indefinite.
Allowable Subject Matter
Claims 3-5, 9, 12, 15, and 22 are allowed.
Claim 17 would be allowable if rewritten to overcome the rejection(s) under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), 2nd paragraph, set forth in this Office action and to include all of the limitations of the base claim and any intervening claims.
The following is an examiner’s statement of reasons for allowance: There is no prior art which teaches or provides a suggestion or motivation to develop, the claimed degron bound using the claimed linkers to the specific compounds of Claim 9 (See STN Search, Search Notes). The closest prior art comes from Fan (US 2020/0157078; Filing Date: 21 November 2019) and Crew (US 2018/0155322; Publication Date: 7 June 2018). Fan and Crew teach bifunctional compounds which contain the claimed degron attached using linkers of the examined application bound to derivatives of tamoxifen, but do not suggest that tamoxifen can be substituted in place for these derivatives. There is no reasonable expectation of success in substituting tamoxifen in place for these compounds as this substitution will change the steric properties of the compound, and alter the properties of the linking group, which is crucial in the ability for the compound to interact with both the target protein and E3 ubiquitin ligase. As the compounds are free of prior art, their compositions and use in methods to modulate cereblon, modulate proteasomal degradation of a protein, or modulating sequestration of a protein to the proteasome are similarly free of prior art.
Any comments considered necessary by applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Conclusion
Claims 3-5, 9, 12, 15, and 22 are allowed.
Claims 16, 17 and 20 are rejected.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHILLIP MATTHEW RZECZYCKI whose telephone number is (703)756-5326. The examiner can normally be reached Monday Thru Friday 730AM-5PM EST.
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/P.M.R./ Examiner, Art Unit 1625 /Andrew D Kosar/Supervisory Patent Examiner, Art Unit 1625