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 .
Non-Final Rejection
The Status of Claims:
Claims 1-20 are pending.
Claims 1-20 are rejected.
DETAILED ACTION
1. Claims 1-20 are under consideration in this Office Action.
Priority
2. It is noted that this application has a priority of 63517604 08/03/2023.
Drawings
3. The drawings filed on 8/02/24 are accepted by the examiner.
IDS
4. None.
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 1-20 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for making salts of the claimed compounds, does not reasonably provide enablement for making hydrates of the claimed compound of formula I. The specification does not enable any person skilled in the art of synthetic organic chemistry to make the invention commensurate in scope with these claims. “The factors to be considered [in making an enablement rejection] have been summarized as a) the quantity of experimentation necessary, b) the amount of direction or guidance presented, c) the presence or absence of working examples, d) the nature of the invention, e) the state of the prior art, f) the relative skill of those in that art, g) the predictability or unpredictability of the art, h) and the breadth of the claims”, In re Rainer, 146 USPQ 218 (1965); In re Colianni, 195 USPQ 150, Ex parte Formal, 230 USPQ 546. In the present case the important factors leading to a conclusion of undue experimentation are the absence of any working example of a formed solvate, the lack of predictability in the art, and the broad scope of the claims.
c) There is no working example of any hydrate or solvate formed. The claims are drawn to hydrates, yet the numerous examples presented all failed to produce a hydrate. These cannot be simply willed into existence. As was stated in Morton International Inc. v. Cardinal Chemical Co., 28 USPQ2d 1190 “The specification purports to teach, with over fifty examples, the preparation of the claimed compounds with the required connectivity. However ... there is no evidence that such compounds exist... the examples of the '881 patent do not produce the postulated compounds... there is ... no evidence that such compounds even exist.” The same circumstance appears to be true here. There is no evidence that solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that hydrates or solvates can be made, or limit the claims accordingly.
g) The state of the art is that is not predictable whether hydrates or solvates will form or what their composition will be. In the language of the physical chemist, a solvate of organic molecule is an interstitial solid solution. This phrase is defined in the second paragraph on page 358 of West (Solid State Chemistry). West, Anthony R., "Solid State Chemistry and its Applications, Wiley, New York, 1988, pages 358 & 365. The solvent molecule is a species introduced into the crystal and no part of the organic host molecule is left out or replaced. In the first paragraph on page 365, West (Solid State Chemistry) says, “it is not usually possible to predict whether solid solutions will form, or if they do form what is their compositional extent". Thus, in the absence of experimentation one cannot predict if a particular solvent will solvate any particular crystal. One cannot predict the stoichiometery of the formed solvate, i.e. if one, two, or a half a molecule of solvent added per molecule of host. In the same paragraph on page 365 West (Solid State Chemistry) explains that it is possible to make meta-stable non-equilibrium solvates, further clouding what Applicants mean by the word solvate. Compared with polymorphs, there is an additional degree of freedom to solvates, which means a different solvent or even the moisture of the air that might change the stabile region of the solvate.
MPEP 2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here. Thus, undue experimentation will be required to practice Applicants' invention.
Claims 16-18 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating acute lymphoblastic leukemia
does not reasonably provide enablement for treating any disease or disorder associated with mitogen-activated protein kinase 7 (MEK7) activity in a subject in need or any cell proliferative disease or disorder or any cancers. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to use the invention commensurate in scope with these claims.
The specification falls short because data essential for treating many types of cancers such as melanoma, colon cancer, lung cancer, pancreatic cancer, , breast cancer, brain tumor, gastric cancer, liver cancer, ovarian cancer, gastrointestinal cancer, leukemia, melanoma, multiple myeloma, lymphoma, soft tissue sarcoma, , pancreas cancer, renal cancer, bladder cancer, uterus cancer, and many other types of any disease or disorder associated with mitogen-activated protein kinase 7 (MEK7) activity in a subject in need or any cell proliferative disease or disorder or any cancers by administering to a subject in need thereof a therapeutically effective amount of a compound having a formula I, or a salt or hydrate is not described in the specification.
Moreover, the claim 18 sets forth t he method of claim 17, wherein the cell proliferative disease or disorder is cancer.
However, there are more than 3000 cancers. Applicants have not identified a specific compound capable of treating “cancers” broadly. Thus, the existence of such a “silver bullet” is contrary to our present understanding in oncology. Even the most broadly effective anti-tumor agents are only effective against a small fraction of the vast number of different cancers known. This is true in part because cancers arise from a wide variety of sources, such as viruses (e.g. EBV, HHV-8, and HTLV-1), exposure to chemicals such as tobacco tars, genetic disorders, ionizing radiation, and a wide variety of failures of the body’s cell growth regulatory mechanisms. The specification falls short because data essential for treating all kinds of cancers is not described in the specification. In the absence of specific malignant tumors or otherwise, data showing inhibition of the multiplication of cancer cells, such a broad assertion is not believable in view of the contemporary knowledge of the art. 34 USPQ 2d, 1436 (Fed Cir. 1995) . See also, MPEP 2107.01, 2107.02. 2107.03, 2164.01©, 2164.04, 2164.07.
Different types of cancers affect different organs and have different methods of growth and harm to the body, and different vulnerabilities. Thus, it is beyond the skill of oncologists today to get an agent to be effective against cancers generally, evidence that the level of skill in this art is low relative to the difficulty of such a task. See also, In re Joller, 206 USPQ 885(CCPA 1980).
In In re Wands, 8 USPQ2d 1400 (1988), factors to be considered in determining whether a disclosure meets the enablement requirement of 35 U.S.C. § 112, first paragraph, have been described. They are:
1. the nature of the invention,
2. the state of the prior art,
3. the predictability or lack thereof in the art,
4. the amount of direction or guidance present,
5. the presence or absence of working examples,
6. the breadth of the claims,
7. the quantity of experimentation needed, and
8. the level of the skill in the art.
The Nature of the Invention
The nature of the invention in claims 16-18 is as followed:
16. A method for treating a disease or disorder associated with mitogen-activated protein kinase 7 (MEK7) activity in a subject in need thereof, the method comprising administering to the subject the compound of claim 1.
17. The method of claim 16, wherein the disease or disorder is a cell proliferative disease or disorder.
18. The method of claim 17, wherein the cell proliferative disease or disorder is cancer.
The predictability or lack thereof in the art
The instant claimed invention is highly unpredictable as discussed below:
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area is, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the instant claimed invention is highly unpredictable since one skilled in the art would recognize that the inhibitors of mitogen-activated protein kinase 7 (MEK7) activity can cause common side effects of MEK pathway inhibitors (including MEK7 and MEK1/2) include dermatologic reactions: Acneiform or maculopapular rashes, dry skin (xerosis), itchy skin (pruritus), and paronychia (inflammation around the nails) are among the most frequent side effects : gastrointestinal distress: nausea, vomiting, and diarrhea are common and can sometimes be severe; ocular toxicities: MEK inhibition is known to disrupt the blood-retinal barrier and common visual issues include blurred vision, chorioretinopathy, and subretinal fluid accumulation (retinopathy). Furthermore , the modifications of formula I with various substitutes in the specification could result in a significant difference in their properties and activity for treating various cancers.
Hence, in the absence of a showing of correlation between all the well-known cancers encompassed by the instant claims and the effectiveness of the compound of formula I for treating any cancer cells, one of skill in the art is unable to fully predict possible results from the administration of the compound of formula I with various substitutes.
The nature of pharmaceutical arts is that it involves screening in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities. There is no absolute predictability even in view of the seemingly high level of skill in the art. The existence of these obstacles establishes that the contemporary knowledge in the art would prevent one of ordinary skill in the art from accepting any therapeutic regimen on its face.
The amount of direction or guidance present
The direction present in the current specification is that the compound of formula I has a strong inhibition effect against a cancer.
However, the specification is silent and fails to provide enough guidance as to whether or not all the claimed cancers or bystander tumors require only the use of the claimed compound x for all kinds of malignant tumor /or cancer treatment successfully; i.e. the specification fails to provide enough correlation between various claimed cancers and the claimed compound. Also, there is no direction and guidance for how all the treatments of the claimed cancers are directly linked to the claimed compound.
The presence or absence of working examples
Figure 8A illustrates the dose-response cytotoxicity of DK2403 (25) in T-ALL cell lines. Figure 8B illustrates the washout cytotoxicity studies of DK2403.
Figure 8C shows the western blot analysis that demonstrated dose-response (in µM) decreased phosphorylation of JNK and ATF2 in T-ALL cells following treatment with 25. Figure 19 illustrates the DK2403 and erlotinib cytotoxic effects. Erlotinib inhibits cell viability in the KOPT-K1 cell line at higher doses than DK2403, suggesting that inhibition of DK2403-mediated cytotoxicity is caused mainly by MAP2K7-JNK inhibition. 31 But there are no other actual working examples for the treatment for all the heterogeneities of cancers using the claimed compound in the specification. Also, the specification does not contain any pharmacological data regarding the treatments for all the heterogeneities of cancers while using the claimed compound. Thus, the specification fails to provide sufficient working examples as to how the treatment of any disease or disorder associated with mitogen-activated protein kinase 7 (MEK7) activity in a subject in need or any cell proliferative disease or disorder or all the heterogeneities of cancers can be treated successfully by the claimed compound without any unexpected negative effects of using the claimed compound.
The breadth of the claims
The breadth of the claims is that the claimed compound can treat any disease or disorder associated with mitogen-activated protein kinase 7 (MEK7) activity in a subject in need or any cell proliferative disease or disorder or any cancers, without regards as to the clinical side effects of the compound on treating various types of the claimed cancers except for pediatric T-cell acute lymphoblastic leukemia being tested with the claimed compound DK2403 (25) as shown in example and Figs.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine whether or not the claimed compound would provide a beneficial treatment of all the heterogeneities of cancers while treating any types of the claimed cancers.
The level of the skill in the art
The level of skill in the art is high. However, due to the unpredictability in the pharmaceutical art, it is noted that each embodiment of the invention is required to be individually assessed for physiological activity by in vitro and in vivo screening to determine whether or not the claimed compound can be led to exhibit the desired pharmacological activity for treating all the heterogeneities of the claimed cancers.
Thus, the specification fails to provide sufficient support for the treatment of all the heterogeneities of the claimed cancers. As a result, it necessitates one of the skilled artisans in the art to perform an exhaustive search for selecting claimed cancers suitable for the claimed compound in order to practice the claimed invention.
Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001 (3/13/1997), states that “ a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion” and “[p]atent 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”.
Therefore, in view of the Wands factors and In re Fisher (CCPA 1970) discussed above, to practice the claimed invention herein, a person of skill in the art would have to engage in undue experimentation to test whether or not all the claimed cancers can be treated by the claimed compound complex, which is encompassed in the instant claims, with no assurance of success.
The examiner recommends to put the specific cancer to the claims.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
5. Claim(s) 1-20 are rejected under 35 U.S.C. 102(a)(1) as being anticipated clearly Kim et al ( ACS Med. Chem. Lett. 202, April 17, 2023, 14, 606−613).
Kim et al discloses a method of treating pediatric pediatric T-cell acute lymphoblastic leukemia (T-ALL) inherently in the following:
It discloses that DK2403(25) and its pharmaceutical composition thereof potently inhibit MAP2K7 without significantly disruptingthe greater kinome, thereby rendering it an excellent candidate for the study of MAP2K7 in pediatric T-ALL(see page 611, a left col. at the bottom paragraph).
Furthermore, it discloses MAP2K7 Inhibitors and Benzylamine-Derived MAP2K7
Inhibitors in the followings:
PNG
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669
579
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(see page 608, table 1)
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579
603
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(see page 609, table 3). These are identical with the claims.
Conclusion
Claims 1-20 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to TAYLOR V OH whose telephone number is (571)272-0689. The examiner can normally be reached 8:00-5:00.
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/TAYLOR V OH/Primary Examiner, Art Unit 1625 7/21/2026
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