DETAILED ACTION
This office action is in response to applicant’s filing dated January 17, 2024.
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 1-3, 11, 14, 15, 18, 29 - 31, 38, 52, 53, 56, 64, 66, 86, and 125-127 are pending in the instant application. Acknowledgment is made of Applicant’s amendments filed January 17, 2024. Acknowledgment is made of Applicant’s cancelation of claims 4-10, 12, 13, 16, 17, 19-28, 32-37, 39-51, 54, 55, 57-63, 65, 67-85, 87-124 and 128-143.
Priority
The present application is a 371 PCT/US22/11824, filed January 10, 2022, which claims benefit of priority to PCT/CN21/71062, filed January 11, 2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 07/11/2023 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 30 and 66 are objected to because of the following informalities:
claim 30:
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and
claim 66:
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,
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appear to have a typographical error in description of variables (see “or” in the red frame), “or” in marked spots should be crossed out or replaced with “and” or “wherein”.
Appropriate correction is required.
Claims 11, 14, 18, 30, 38, 53, 56, 86 and 125 are 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.
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.
Claims 1 – 3, 15, 29, 31, 52, 64, 66, 126 and 127 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the method of treatment of leukemia or leukemia related inflammation with compounds of formula (I), does not reasonably provide enablement for treating or preventing all MK2 related disorders or any metabolic disorders. 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 /n 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:
1. Nature of the invention and the Breadth of the claims.
The invention is drawn to a method of treating or preventing of any MK2 related disorders or any metabolic disorders with compounds of Formula (I)
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. The breadth of the claims is extensive.
Scope of the compound covered:
The number of compounds encompassed by the formula above is vast since the formula encompasses a large number of possible structural components for each variable of the compound of Formula (I) and as such combinations of the various variables recited in the claims would yield millions of compounds. There are 7 variables combinations, such as X1-3, Y1-3 and Z. Where, e.g. Z variable is defined to be any one of the many different moieties, for e.g. :
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The variables are further expanded by use of terms substituted without defining what the substituents are and as such could encompass any of the millions of moieties known in the art. These compounds encompass molecules that widely vary in the physical and chemical properties such as size, molecular weight, acidity, basicity, and properties that are known in the art to greatly influence pharmacokinetic and pharmacodynamics parameters, not to mention the ability to productively bind to claimed biological target molecules. The claims cover compounds easily in the millions given the number of possible undefined substituents covered by the claims' scope along with varying choices for remaining variables. Each of these compounds is claimed to be useful in the method of treating all types disorders, encompassed by instant claims.
Scope of the diseases covered:
There is a wide range of MK2 related disorders including inflammatory, autoimmune diseases, fibrotic disorders, cancer, neurodegenerative diseases etc. Although those conditions might share some underlying cellular mechanisms, they represent distinct clinical conditions and require specific approach. Furthermore, metabolic disorders is a large group of conditions, often are hereditary and genetic and untreatable. Some metabolic disorders (e.g. Phenylketonuria or Gaucher’s disease), have fundamentally different causes, unrelated to MK2 inhibition pathways.
Moreover, Applicant proposes to prevent all conditions, named above, with all the compounds of Formula (I), where compounds act as MK2 inhibitors.
2. Relative skill of those 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., 807 F.2d at 962. 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 active workers in the fields of Medicinal chemistry, biology, biochemistry, and pharmacology, as well as the high degree of sophistication required to solve problems encountered in the art, the Examiner finds that a person of ordinary skill in the art would have at least a college degree in one of the fields identified above and at least four years of work experience; i.e. a masters or doctorate level scientist.
3. The predictability or unpredictability of the art and the state of the prior art.
The instantly claimed invention is highly unpredictable. As noted above, the invention proposes to treat variety of conditions, some of which are unrelated or genetic, with the same drugs. There is no common mechanism by which all metabolic diseases arise. Accordingly, treatments for these diseases are normally tailored to the particular type of disease as there is no, and there can be no universal drug to treat all named above conditions in general. Accordingly, the unpredictability of treating or furthermore preventing any of mentioned above disorders with MK2 inhibitors is very high. 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); 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: Phoa et al (Cancers (Basel). 2020 Mar 11;12(3):654), Suarez-Lopez et al (iScience. 2021 Nov 7;24(12):103406) and Yang et al (Front. Immunol. 16:1712589. doi: 10.3389/fimmu.2025.1712589).
With regards to unpredictability, Phoa et al., cited for evidentiary purposes teaches: targeting MK2 in tumors with TP53 mutations may accelerate disease progression. These findings are highly relevant since TP53 mutations occur in over 50% of all cancers (abstract). In line with p53wt tumor-suppressive functions, MK2 inhibition in p53wt cells induced apoptosis (in up to 30% cells) and senescence (in ~80% cells; Figure 3). However, the stabilization of p53 mutants (Figure 4E) is necessary for their oncogenic activities. As such, MK2 inhibition might result in two opposite effects, depending on the status of the TP53 gene (page 10, 2.6). During their studies Phoa et al. revealed the fact that the MK2-dependent degradation of p53 appears to be a general regulatory mechanism for both wild-type and mutated p53. While wild-type p53 is a potent tumor suppressor, mutated p53 proteins exhibit gain-of-function oncogenic properties (page 12, “discussion”). The stability of p53 mutants is further amplified upon MK2 inhibition. Thus, the administration of MK2 inhibitors to patients with mutated p53 could have dire consequences.
Phoa et al. conclude that, taken together, the cellular response to MK2 inhibition appears remarkably flexible and depends on the cell type, the genetic background and the type of external stimuli (page 12, “discussion”).
Furthermore, with regards to unpredictability, Suarez-Lopez et al., cited for evidentiary purposes teaches: Inflammatory bowel diseases (IBDs) are genetically complex and exhibit significant inter-patient heterogeneity in disease presentation and therapeutic response. Mouse models of IBD exhibit variable responses to inhibition of MK2 (summary). After 3 weeks of treatment, and even after confirmed targeting of MK2 signaling pathway (Figure 1A), TNFΔARE/+ mice showed no evidence of improvement after MK2 inhibitor (ATI-450) treatment. Pathology scores (which semi-quantitatively summarize key aspect of chronic ileitis) were not significantly different between treated and untreated mice (Figure 1B). This finding was in clear contrast to ATI-450 treatment outcome in the TCT model of colitis. In this model administration of ATI-450 to animals with colitis resulted in improvement of pathology scores. Based on data obtained from experiments, Suarez-Lopez et al. concludes: although MK2 is activated during inflammation in the TNFΔARE model and ATI-450 inhibits MK2, inhibition of the pathway is not associated with an abrogation of cellular or molecular inflammatory phenotypes (page 4, 1st and 2nd paragraph). Therefore, further effort would be to focus on deconvoluting the mechanism through which MK2 regulate and contribute to the inflammatory state of the intestinal tissues (page 14, “limitations”).
Moreover, with regards to unpredictability Yang et al., cited for evidentiary purposes in later dated reference teaches: MK2 knockout mice had significantly reduced TNFα release and the MK2/MK3 double knockout mouse exhibited significantly more inhibition than MK2 knockout mice. This suggests that MK2 is the major MAPKAP kinase regulating TNFα production but does not preclude that MK3 may play an additional role (page 3, left column, 1st paragraph). Combined knockout indicates a cooperativity between TNFα MK2 and MK3 or MK5 in the release of given that the effect is more pronounced than any of the single gene knockouts alone. Summarizing their findings Yang et al. conclude: The combined data, along with the in vitro data, may suggest that inhibition of either MK3 or MK5 is needed in addition to MK2 to achieve full suppression of the pathway. This complex molecular interplay between p38 MAP kinase, MK2, MK3 and MK5 suggests that selective targeting of a single MAPKAP kinase family may be insufficient to fully blunt inflammatory responses. Hence, a broader modulator that antagonizes or degrades MK2, MK3 and/or MK5 may well be required for the effective suppression of inflammation (pages 9 – 10).
These articles plainly demonstrate that the art of developing and testing therapies to treat any and all types of diseases with all the compounds encompassed by instant claims is unpredictable. More generally, the invention is directed toward medicine and is therefore physiological in nature. It is well established that “the scope of enablement varies inversely with the degree of unpredictability of the factors involved,” and physiological activity is generally considered to be an unpredictable factor. See In re Fisher, 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970).
4. Amount of guidance/existence of working examples.
The instant claims, directed to a method of treating or preventing any MK2 related disorders or any metabolic disorders with compounds of Formula (I) are extremely broad in contrast with the specification that only provides data, showing therapeutic activity of 137 compounds, encompassed by Formula (I) (Table 16) on THP-1 cell line. The specification fails to provide adequate support for effectively treating or preventing any metabolic disorders. Applicant fails to provide any information sufficient to practice the claimed invention, absent undue experimentation. Although specification provides general direction or guidance of:
- route of administrations e.g.: “A pharmaceutical composition (preparation) can be administered to a subject by any of a number of routes of administration including, for example, orally (suspensions, tablets, capsules etc.), anally, rectally or vaginally, parenterally (including intramuscularly, intravenously, subcutaneously or intrathecally); nasally etc.” (page 58, 2nd paragraph);
- dosages e.g.:” dosage levels of the active ingredients in the pharmaceutical compositions may be varied so as to obtain an amount of the active ingredient that is effective to achieve the desired therapeutic response for a particular patient, without being toxic to the patient” (page 66, 1st paragraph);
- regimen e.g.: “compounds of the invention may be used alone or conjointly administered with another type of therapeutic agent; the different therapeutic compounds can be administered either in the same formulation or in a separate formulation, either concomitantly or sequentially (page 67, 3rd paragraph), necessary to treat all of the various diseases encompassed by the claims, the directions are very broad and include vast variety of known formulations.
While experimentation is presented for treatment of leukemia, there is no experimentation or mechanism of action presented or discussed in the specification regarding treatment of the conditions that are not leukemia. Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
5. 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 all the compounds of general Formula (I), which are useful in the treatment of leukemia or inflammation associated with leukemia, could be predictably used as treatment for all MK2 related disorders or any metabolic disorders. 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 treatment of all MK2 related disorders or any metabolic disorders, except for the treatment of inflammation, related to leukemia. A review of the state of the art fails to reveal that all the compounds encompassed by Formula (I) in combination with additional therapeutic agent are useful as a therapeutic for the treatment of all MK2 related disorders or any metabolic disorders, except for the treatment of leukemia or inflammation, related to leukemia. Determining if any particular claimed compound would treat any particular 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.
Conclusion
Claims 1 – 3, 15, 29, 31, 52, 64, 66, 126 and 127 are rejected.
Claims 11, 14, 18, 30, 38, 53, 56, 66, 86 and 125 are objected to.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ELENA V VISHNYAKOVA whose telephone number is (571)272-3781. The examiner can normally be reached 7:30am - 5pm ET.
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/E.V.V./ Examiner, Art Unit 1691
/SAVITHA M RAO/ Primary Examiner, Art Unit 1691