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 Claims
Claims 1-7, 9, 11, 13-16 and 18 are pending in the instant application. Claims 8, 10, 12, 17 and 19 are cancelled and claims 1-7, 11, 13 and 18 are amended via the amened filed June 11th, 2026.
Priority
This is a 35 U.S.C. 371 National Stage filing of International Application No. PCT/CN2021/134929 filed December 2nd, 2021, which claims priority under 35 U.S.C. 119(a-d) to CN202110758372.0, filed July 5th, 2021 and CN202011389148.0, filed December 2nd, 2020. Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d).
Withdrawn Objections
Applicant’s arguments and amendments, filed June 11th, 2026, with respect to objection of claim 1 have been fully considered and are persuasive. The objection of claim 1 has been withdrawn.
Applicant has overcome this objection by amending the claim to replace each instance of “by from” with “with”, replace each instance of “containing from one to two heteroatoms selected from N” with “containing one to two N atoms” and insert “and” before “C1-6 alkyl” in the definition of R2a.
Applicant’s arguments and amendments, filed June 11th, 2026, with respect to objection of claims 2-4 have been fully considered and are persuasive. The objection of claims 2-4 has been withdrawn.
Applicant has overcome this objection by amending the claims to replace each instance of “by from” with “with” and replace each instance of “containing from one to three heteroatoms selected from N” with “containing one to three N atoms”.
Applicant’s arguments and amendments, filed June 11th, 2026, with respect to objection of claim 5 have been fully considered and are persuasive. The objection of claim 5 has been withdrawn.
Applicant has overcome this objection by clearly striking through each of the repeated structures in the claim.
Applicant’s arguments and amendments, filed June 11th, 2026, with respect to objection of claims 6-7 have been fully considered and are persuasive. The objection of claims 6-7 has been withdrawn.
Applicant has overcome this object by amending the claims to insert “and” before the last option in the Markush grouping.
Withdrawn Rejections
Applicant’s arguments and amendments, filed June 11th, 2026, with respect to 112(d) rejection of claims 2, 5-6 and 13 have been fully considered and are persuasive. The 112(d) rejections of claims 2, 5-6 and 13 has been withdrawn.
Applicant has overcome the 112(d) rejections by amending claim 2 to recite “one to two R2a groups”, deleting the inconsistencies in R2 and R3 in claims 5-6 and amending claim 13 to have dependency on claim 1 instead of claim 6.
Maintained Rejections
Applicant's arguments filed June 11th, 2026, with respect to the 112(a) enablement rejection of claims 11 and 17-19 have been fully considered but they are not persuasive.
See response to remarks.
Response to Remarks
Applicant’s arguments regarding the claim objections and 112(d) rejections are moot and will not be addressed as the objections and 112(d) rejections have been overcome by Applicant’s amendments.
Applicant’s arguments are not persuasive regarding the enablement rejection and the 112(a) rejection of claims 11 and 18 are maintained for the reasons below.
On p. 20-21 of the remarks, Applicant argues that as the specification provides data that shows the effect of compounds of formula (I) against Human osteosarcoma cells and leukemia cells and inhibiting the TYK2 signal pathway, the newly amended claims 11 and 18 are now enabled.
In response, as Applicant is still claiming the prevention of inflammatory disease, autoimmune disease or osteosarcoma, the methods remain not enabled.
As stated in the previous Office action, The specification provides data that shows the effect of compounds of formula (I) against Human osteosarcoma cells and leukemia cells and inhibiting the TYK2 signal pathway. Additionally, Szilveszter teaches that TYK2 is associated with autoimmune disorders and inflammatory diseases (abstract). Thus, the data provided shows the effect of a compound of instant formula (I) with very specific disease/disorders, cancer, autoimmune disorder and inflammatory disease. The specification provides no particular direction or guidance for determining the particular administration regimens (e.g., timing, administration routes, etc.) necessary to prevent and/or treat all disorders/diseases encompassed by the claims, particularly in humans. At best, an “effective amount” is exemplified as “the amount that can effectively achieve the desired therapeutic or preventive effect in terms of both dose and time” (paragraph [0057]). There is no experimentation or mechanism of action presented or discussed in the specification regarding the prevention and treatment of all diseases/disorders mediated by TYK2, that is not the treatment of inflammatory disease, autoimmune disease and cancer.
As there is no current guidance in the art and the specification merely provides data that shows the effect of compounds of formula (I) against Human osteosarcoma cells and leukemia cells, the methods of prevention of instant claims 11 and 18 are still not enabled by the instant disclosure. As such, the 112(a) rejection of claims 11 and 18 is maintained.
Maintained Claim Rejections - 35 USC § 112(a)
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(s) 11 and 18 stand 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 inflammatory disease, autoimmune disease and osteosarcoma comprising administering a compound of formula (I), the specification does not reasonably provide enablement for the prevention of inflammatory disease, autoimmune disease and osteosarcoma comprising administering a compound of formula (I).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. This is a scope of enablement rejection.
To be enabling, the specification of the patent application 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 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
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 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). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
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:
5A. The nature of the invention, state and predictability of the art, and relative skill of those in the art
The invention relates to methods of preventing and/or treating inflammatory disease, autoimmune disease and osteosarcoma comprising administering a compound of formula (I).
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant’s invention would generally be a physician with a M.D. degree and several years of experience.
The factor is outweighed, however, by the unpredictable nature of the art. It is well established that “the scope of enablement varies with the degree of unpredictability of the factors involved” and physiological activity is considered to be an unpredictable factor. See In re Fisher, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved); Nationwide Chemical Corporation, et. al. v. Wright, et. al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances); Ex parte Sudilovsky 21 USPQ2d 1702 (Applicant’s invention concerns pharmaceutical activity.); In re Wright 27 USPQ2d 1510 (the physiological activity of RNA viruses was sufficiently unpredictable that success in developing specific avian vaccine was uncertain).
As illustrative of the state of the art, the examiner cites Gerstenberger (J. Med. Chem. 2020, 63, 22, 13561–13577), Kunnumakkara et al (Experimental Biology and Medicine, 2019; 244:663-689) and Szilveszter et al (Front Immunol. 2019 Aug 9;10:1862).
With regard to the unpredictability of targeting TYK2, Gerstenberger, cited for evidentiary purposes, teaches to date, a large number of specific small-molecule inhibitors have been developed as TYK2 kinase inhibitors, and they are different in structure, efficacy, selectivity, cell permeability, and binding mode; most of the compounds are JAK kinase inhibitors (See Figure 1).
Furthermore, with regard to unpredictability of cancer preventability, Kunnumakkara, cited for evidentiary purposes, teaches cancer is a group of more than 200 neoplastic diseases caused by diverse deregulated cell signaling cascades (page 633, left, 1st paragraph); consumption of tobacco and alcohol, obesity, insufficient physical activity, exposure to ultraviolet radiation, and various dietary factors which include insufficient fruit, non-starchy vegetables, and fiber; red/processed meat are predicted to be strongly associated with the risk of diverse cancer types; cancer occurs as a result of the dysregulation of as many as 500 different genes which may happen over a very long duration of time (20–30 years) till the symptoms become apparent (page 633, right, last bridge paragraph). Kunnumakkara further teaches there exists a missing connection between preclinical data and clinical findings; although, a significantly huge amount of money is spent in the pre-clinical settings for target validation and drug optimization, most of the therapies fail in the clinical trials; this can be due to the reason that the models used in the pre-clinical setting are not the adequate ones to effectively mimic human responses (page 664, right, 2nd paragraph); although highly convenient, cancer cell line models are associated with several limitations as well; for example, existence of genomic instability which may result in differences between the original tumor and the respective cell line, culture conditions that can alter the morphology, gene expression pattern, genomic profile, cellular pathways and culture environment from that of the original tumor, loss of natural tumor heterogeneity; the generic transformations that occur upon culturing of the cancer cells are not restored when regrown in vivo; and cancer cells in the in vitro condition grow in absence of stroma which include lymphatic vessels and blood, associated fibroblasts and immune cells, and lack a complex extracellular matrix; therefore, in vitro data often exhibits fundamental mismatch with those obtained from clinical findings and hence this can be regarded as one prime reason behind the failure of novel drug development (page 665, last bridge paragraph). Kunnumakkara teaches the foremost shortcomings of the use of animal models are their inability to recapitulate the link between the tumor and its microenvironment completely and the requisite of an immunocompromised host; basically, these animal models do not have the ability to reflect all the features of human cancer impeccably. Kunnumakkara teaches despite the advances in understanding of cancer biology and deriving different novel therapeutic targets, the translation of these understanding into therapies is poor due to higher failure rate (90%). The high failure rate could be due to non-consideration of factors such as clinical translation, drug delivery, drug pharmacokinetics, pre-clinical models, and tumor physiology, which are critical factors.
These articles plainly demonstrate that the art of developing and testing TYK2 inhibitors, particularly for use in humans, is extremely unpredictable, particularly in the case of a single compound or genus of compounds being used to treat any and all diseases mediated by the TYK2.
5B. The breadth of the claims
Claim(s) 11 and 18 are very broad in terms of the type of diseases being prevented or treated and the types of compounds administered: inflammatory disease, autoimmune disease and osteosarcoma are claimed to be prevented and/or treated with any compound of formula (I).
5C. The amount of direction or guidance provided and the presence or absence of working examples
The specification provides data that shows the effect of compounds of formula (I) against Human osteosarcoma cells and leukemia cells and inhibiting the TYK2 signal pathway. Additionally, Szilveszter teaches that TYK2 is associated with autoimmune disorders and inflammatory diseases (abstract). Thus, the data provided shows the effect of a compound of instant formula (I) with very specific disease/disorders, cancer, autoimmune disorder and inflammatory disease. The specification provides no particular direction or guidance for determining the particular administration regimens (e.g., timing, administration routes, etc.) necessary to prevent and/or treat all disorders/diseases encompassed by the claims, particularly in humans. At best, an “effective amount” is exemplified as “the amount that can effectively achieve the desired therapeutic or preventive effect in terms of both dose and time” (paragraph [0057]). There is no experimentation or mechanism of action presented or discussed in the specification regarding the prevention and treatment of all diseases/disorders mediated by TYK2, that is not the treatment of inflammatory disease, autoimmune disease and cancer.
5D. The quantity of experimentation necessary
Because of the known unpredictability of the art (as discussed supra) and in the absence of experimental evidence commensurate in scope with the claims, the skilled artisan would not accept that any compound of formula (I) could be predictably used as prevention and/or treatment for all related diseases mediated by TYK2.
Genentech Inc. vs. Nova Nordisk states, "[A] patent is not a hunting license. It is not a reward for a search but a compensation for its successful conclusion and 'patent protection' is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable" (42 USPQ 2d 1001, Fed. Circuit 1997).
As noted above, none of the experimentation provided is drawn to the prevention and/or treatment of related diseases mediated by TYK2 that is not the treatment of inflammatory disease, autoimmune disease and cancer. A review of the state of the art fails to reveal that TYK2 inhibitors are useful as a therapeutic for the treatment of any diseases mediated by TYK2, except for inflammatory disease, autoimmune disease and cancer. Determining if any particular claimed compound would treat any particular cancerous disease state would require synthesis of the compound, formulation into a suitable dosage form, and subjecting it to clinical trials or to testing in an assay known to correlate to clinical efficacy of such treatment. This is undue experimentation given the limited guidance and direction provided by Applicants. As noted supra, even in vitro and in vivo assays do not always correlate to efficacy in humans and are not generally predictive of clinical efficacy.
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Closest Prior Art
As stated in the previous Office action, the closest prior art in terms of structural similarity to the compounds of instant formula (I) is Guillemont et al (WO 2007/113254). Guillemont teaches the following compound (page 34, compound 23):
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However, there are multiple differences between the prior art disclosure and the instant invention. First, the prior art compound has a pyrimidine ring where formula (I) requires a pyridazine ring or a pyridine ring. Also, the prior art does not allow for the ring to be wither of the options as required by instant formula (I). Further, the prior art only teaches the compound above and it’s utility in HIV replication inhibiting properties and no mention of its application within the TYK2. As such, the prior art disclosure does not teach the necessary motivation to alter the compound above to arrive at a compound of instant formula (I).
Another close prior art in terms of structural similarity to the compounds of instant formula (I) is Kitamura et al (US 2011/0237590 A1). Kitamura teaches the following compound (paragprah [1788], example 338):
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However, there are multiple differences between the compound of the prior art and a compound of instant formula (I). There is an extra -CH2- in the prior art compound, where instant formula (I) requires a direct connection to R3. Also, R2 cannot be substituted with a heterocycle. Further, the prior art teaches the compounds utility as a JAK3 inhibitor not a TYK2 inhibitor.
In view of the above, the compounds of the instant invention are novel and nonobvious.
Conclusion
Claims 1-7, 9 and 13-16 are allowed and claims 11 and 18 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 Anna Grace Kuckla whose telephone number is (703)756-5610. The examiner can normally be reached Monday-Friday 7:30-5.
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/A.G.K./Examiner, Art Unit 1626
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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