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 1-12 are pending.
Claims 1-12 are rejected.
Claim 12 is objected.
DETAILED ACTION
1. Claims 1-12 are under consideration in this Office Action.
Priority
2. This application is a 371 of PCT/CN2021/095329 05/21/2021, which has a foreign priority document CHINA CN202010477110.2 05/29/2020.
Drawings
3. None. .
IDS
4. The IDS filed on 11/23/22 have been reviewed by the examiner
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 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.
Claim Objections
Claim 12 is objected to because of the following informalities:
In claim 12 , the terms” rheumatoid arthritis” have been repeated twice. This is improper. Appropriate correction is required.
Claim Rejections - 35 USC § 112
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.
Claims 1-7 and 9-11 are 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 pre-AIA the applicant regards as the invention.
Claims 1-7 and 9-10 are rejected on the judicially-created basis that it contains an improper Markush grouping of alternatives. See In re Harnisch, 631 F.2d 716, 721-22 (CCPA 1980) and Ex Parte Hozumi, 3 USPQ2d 1059, 1060 (Bd. Pat. App. & Int. 1984). The improper Markush includes species of the claimed invention that do not share both a substantial structural feature and a common use that flows from the substantial structural feature. The members of the improper Markush grouping do not share a substantial feature and /or a common use that flows from the substantial structural feature for the following reasons :
In claim 1,
1. (Currently Amended) A compound of formula I or a stereoisomer or optical isomer, a
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I wherein, A is independently selected from the group consisting of C(=0), -C(=0)O-, C(=0)NH, N-Rb,O, S, SO, and S02;B is independently selected from the group consisting of bond, C(=0), N-Rb, C(Rc)2, C(=O)O-, O,S, SO, and S02;ring C is independently selected from thea substituted or unsubstituted ring selected from the group consisting of 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; X is independently selected from the group consisting of N and CRd;Y is independently selected from the group consisting of C(=0), N-Rb, C(Rc)2, C(=0)O-,O,S, SO, and SO2;Z is independently selected from the group consisting of bond, N-Rb,O,S, and C(Rc)2;W is independently selected from the group consisting of C(Rc)2, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl, and Li-(CH2)n-L2; wherein Li is independently selected from the group consisting of absent, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl, L2 is independently selected from the group consisting of N-Rb, C(=O)O-, O, S, SO, and 502;Rb is independently selected from the group consisting of H, and C1-C6 alkyl; Rc is each independently selected from the group consisting of H, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfonyl, sulfinyl, amido, sulfonamido, ester group, C1-C6 alkyl, C1-C6 alkoxy, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; R1, R2, R3, R4, Rs, R6, R7 and Rd are each independently selected from the group consisting of H, D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfonyl, sulfinyl, amido, sulfonamido, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; or, Ri and R2 together with the atoms to which they are attached form thea substituted or unsubstituted ring selected from the group consisting of 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, and C3-C10 cycloalkyl; the H atom in -(CH2)m- and -(CH2)n- can beis optionally substituted by one or more Ra; the "substituted" refers to being substituted by one or more groups selected from the group consisting of D, halogen, amino, nitro, hydroxyl, cyano, carboxyl, sulfonyl, sulfinyl, amido, sulfonamido, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; unless otherwise specified, the above alkyl, alkoxy, alkenyl, alkynyl, heterocycloalkyl, cycloalkyl, heteroaryl, and aryl may beis further optionally substituted by one or more Ra, wherein each Ra is independently selected from the group consisting of halogen, amino, nitro, hydroxyl, sulfydryl, cyano, carboxyl, sulfonyl, sulfinyl, amido, sulfonamido, ester group, formyl, formamido, C1-C6 alkyl, C1-C6 alkoxy, C2-C6 alkenyl, C2-C6 alkynyl, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; m is 1, 2,3,4, 5 or 6; and n is 0, 1, 2, or 3.
The variables of C and W in the formula (I ) and those of L1, R1, R2, R3, R4, R5, R6, R7, Ra, Rc, Rd in the formula (I) are described in the followings:
Ring C is 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl; whereas W is independently selected from the group consisting of C(Rc)2, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, C6-C12 aryl, or L1-(CH2)n-L2; wherein L1 is independently selected from the group consisting of absent, 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, and C6-C12 aryl, wherein L1 is 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, or C6-C12 aryl; Rc is 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, or C6-C12 aryl; each of R1, R2, R3, R4, R5, R6, and R7 is 3-10 membered heterocycloalkyl, C3-C10 cycloalkyl, 5-12 membered heteroaryl, or C6-C12 aryl ; combing R1 with R2 to form a ring is selected from the group consisting of 5-6 membered aryl or heteroaryl, 3-10 membered heterocyclyl, and C3-C10 cycloalkyl.
According to the specification, it describes that he term "cycloalkyl" refers to a cyclic alkyl containing a specific number of C atoms such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl; the 3-10 membered heterocyclyl may be oxetanyl, azetidinyl, tetrahydro-2H-pyranyl, piperidinyl, piperazinyl, tetrahydrofuranyl, morpholinyl and pyrrolidinyl; "aryl" refers to preferably phenyl, naphthyl; "heteroaryl" refers to pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, pyrrolyl, pyrazolyl, imidazolyl, (1,2,3)-triazolyl, and (1,2,4)-triazolyl, tetrazolyl, furyl, thienyl, isoxazolyl, thiazolyl, oxazoly
From the above, it is estimated that the C ring with a subset of numerous substituents at least 25 different compounds and the W ring contains at least 25 different compounds, whereas each of L1, R1, R2, R3, R4, R5, R6, R7, Ra, Rc, and Rd contains at least 25 different ring compounds; the claims 1-7 do read on an extremely high number of possible species due to all the permutations and combinations in terms of mathematically speaking. There is no substantial structural feature (for example a common core) shared by all species; furthermore, there is no indication that the species share a specific common on utility.
In response to this rejection, Applicant should either amend the claims to recite only individual species or grouping of species that share a substantial structural feature as well as a common use that flows from the substantial structural feature, or present a sufficient showing that the species recited in the alternative of the claims in a fact share a substantial structural feature as well as a common use that flows from the substantial structural feature.
In claims 1-9, 11, the term ““prodrug " is recited. This expression is vague and indefinite because the specification does not elaborate what is meant by the term “prodrug " and in the claims.
In claims 10-11, the phrases” diseases associated with the activity or expression of JAK kinase” and “ a disease related to the activity or expression of JAK kinase” are recited. These are vague and infinite because the claims do not clarify how closely the disorder is related to the activity or expression of JAK kinase or how closely the disorder is associated with the activity or expression of JAK kinase. The examiner recommends to put the specific names of the diseases.
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 1-9, and 11 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 making salts of the claimed compounds, does not reasonably provide enablement for making all kinds of solvates of the claimed compounds. 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 how any hydrate or solvate formed. The claims are drawn to solvates, yet the numerous examples presented all failed to produce a solvate. 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 all kinds of solvates of these compounds actually exist; if they did, they would have formed. Hence, applicants must show that solvates can be made, or limit the claims accordingly.
g) The state of the art is that is not predictable whether 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 stoichiometry 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.
h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula I as well as the presently unknown list of solvents embraced by the term "solvate". Thus, the scope is broad.
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 all kinds of solvates or hydrates of the claimed compounds with 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.
Claims 10-12 are rejected under 35 U.S.C. 112, first paragraph, because the specification, while being enabling for treating specific diseases, does not reasonably provide enablement for preventing diseases associated with the activity or expression of JAK kinas or preventing a disease related to the activity or expression of JAK kinase. 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. Applicants are not enabled for preventing any of these diseases. The only established prophylactics are vaccines not the compounds of Formula I such as present here. In addition, it is presumed that “prevention” of the claimed diseases would require a method of identifying those individuals who will develop the claimed diseases before they exhibit symptoms. There is no evidence of record that would guide the skilled clinician to identify those who have the potential of becoming afflicted.
“The factors to be considered [in making an enablement rejection] have been summarized as the quantity of experimentation necessary, the amount of direction or guidance presented, the presence or absence of working examples, the nature of the invention, the state of the prior art, the relative skill of those in that art, the predictability or unpredictability of the art, 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. 1) As discussed above, preventing diseases requires identifying those patients who will acquire the disease before the disease occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) The passages spanning lines 15-19, page 12 list the diseases Applicant intend to treat. 3) There is no working example of such a preventive procedure in man or animal in the specification. 4) The claims rejected are drawn to clinical prevention of diseases associated with the activity or expression of JAK kinas or a disease related to the activity or expression of JAK kinase and are therefore physiological in nature. 5) The state of the art is that no general procedure is art-recognized for determining which patients generally will become prevented from the diseases associated with the activity or expression of JAK kinas or the disease related to the activity or expression of JAK kinase before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in diseases associated with the activity or expression of JAK kinas or the disease related to the activity or expression of JAK kinase with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a compound to be effective for the prevention of diseases associated with the activity or expression of JAK kinas or preventing a disease related to the activity or expression of JAK kinase s generally. Under such circumstances, it is proper for the PTO to require evidence that such an unprecedented feat has actually been accomplished, In re Ferens, 163 USPQ 609. No such evidence has been presented in this case. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs. Novo Nordisk, 42 USPQ2nd 1001, 1006. This establishes that it is not reasonable to any agent to be able to prevent the diseases associated with the activity or expression of JAK kinas or the disease related to the activity or expression of JAK generally. That is, the skill is so low that no compound effective generally against the diseases associated with the activity or expression of JAK kinas or the disease related to the activity or expression of JAK kinase has ever been found let alone one that can prevent such conditions. 7) 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). 8) The claims broadly read on all patients, not just those undergoing therapy for the claimed diseases and on the multitude of compounds embraced by Formula I.
The Examiner suggests deletion of the word “preventing” from the claims.
Claims 1-12 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
In the claim 1-9, 11, the term “ prodrug” is recited. However, the specification has not described how any prodrug or predrug is converted into its active form in the body under any circumstances. This description is essential to the claimed invention because it allows to distinguish identifying characteristics sufficient show that the applicant was in possession of the claimed invention, and the claim, as a whole, may not be adequately described where the invention is described solely in terms of a process of its conversion coupled with its function and there is no described or art-recognized correlation or relationship between the structure of the invention and its functional language. For example, the specification merely mentions that the term “prodrug” or “predrug” refers to any compound which, upon administration to a host, is converted or metabolized to an active compound. Furthermore, Medical dictionary defines the term as a class of drugs, initially in active form, that are converted into active form in the body by normal metabolic processes. There are no examples for the class of prodrugs applicable to the claimed invention; not to mention, how the prodrugs are converted or metabolized to the active compound of the present invention.
Therefore, the specification has failed to describe the subject matter in the claims as to the relationship between the prodrugs and their final active claimed compounds during the preparation process.
The claim 12 sets forth the treatment of cancer generally. However, there never has been a compound capable of treating cancer generally. There are compounds that treat a range of cancers, but no one has ever been able to figure out how to get a compound to be effective against cancer generally, or even a majority of cancers. Thus, the existence of such a “silver bullet” is contrary to our present understanding in oncology. Even the most broadly effective antitumor 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. 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.
When the best efforts have failed to achieve a goal, it is reasonable for the PTO to require evidence that such a goal has been accomplished, In re Ferens, 163 USPQ 609. The failure of skilled scientists to achieve a goal is substantial evidence that achieving such a goal is beyond the skill of practitioners in that art, Genentech vs Novo Nordisk, 42 USPQ2nd 1001, 1006.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement for the scope of “inflammation” generally is not present. For a compound or genus to be effective against inflammation generally is contrary to medical science. Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, causes for the problem, and biochemical pathways that mediate the inflammatory reaction. There is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, C3a, C5a, histamine, assorted leukotrienes and cytokines, and many, many others. Accordingly, treatments for inflammation are normally tailored to the particular type of inflammation present, as there is no, and there can be no “magic bullet” against inflammation generally.
Inflammation is the reaction of vascularized tissue to local injury; it is the name given to the stereotyped ways tissues respond to noxious stimuli. These occur in two fundamentally different types. Acute inflammation is the response to recent or continuing injury. The principal features are dilatation and leaking of vessels, and recruitment of circulating neutrophils. Chronic inflammation or "late-phase inflammation" is a response to prolonged problems, orchestrated by T-helper lymphocytes. It may feature recruitment and activation of T- and B-lymphocytes, macrophages, eosinophils, and/or fibroblasts. The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells. Granulomas are seen in certain chronic inflammation situations. They are clusters of macrophages which have stuck tightly together, typically to wall something off. Granulomas can form with foreign bodies such as aspirated food, toxocara, silicone injections, and splinters.
Otitis media is an inflammation of the lining of the middle ear and is commonly caused by Streptococcus pneumoniae and Haemophilus influenzae. Cystitis is an inflammation of the bladder, usually caused by bacteria. Blepharitis is a chronic inflammation of the eyelids that is caused by a staphylococcus. Dacryocystitis is inflammation of the tear sac, and usually occurs after a long-term obstruction of the nasolacrimal duct and is caused by staphylococci or streptococci. Preseptal cellulitis is inflammation of the tissues around the eye, and Orbital cellulitis is an inflammatory process involving the layer of tissue that separates the eye itself from the eyelid. These life-threatening infections usually arise from staphylococcus. Hence, these types of inflammations are treated with antibiotics.
Certain types of anti-inflammatory agents, such as non-steroidal anti-inflammatory medications (Ibuprofen and naproxen) along with muscle relaxants can be used in the non-bacterial cases. The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for inflammation. It establishes that it is not reasonable to any agent to be able to treat inflammation generally.
Moreover, enablement for “ the treatment of inflammatory disease such as Alzheimer’s disease “.by a compound of formula I is not present. The specification merely mention the use of the compound of formula I in the treatment of Alzheimer’s disease without any sufficient examples and tests.
Alzheimer's disease (AD), also referred to simply as Alzheimer's, is a chronic neurodegenerative disease that usually starts slowly and gradually worsens over time. It is the cause of 60–70% of cases of dementia. The most common early symptom is difficulty in remembering recent events. As the disease advances, symptoms can include problems with language, disorientation (including easily getting lost), mood swings, loss of motivation, not managing self care, and behavioral issues. As a person's condition declines, they often withdraw from family and society. Gradually, bodily functions are lost, ultimately leading to death. Although the speed of progression can vary, the typical life expectancy following diagnosis is three to nine years.The cause of Alzheimer's disease is poorly understood. About 70% of the risk is believed to be inherited from a person's parents with many genes usually involved. Other risk factors include a history of head injuries, depression, and hypertension The disease process is associated with plaques and neurofibrillary tangles in the brain. A probable diagnosis is based on the history of the illness and cognitive testing with medical imaging and blood tests to rule out other possible causes. Initial symptoms are often mistaken for normal ageing. Examination of brain tissue is needed for a definite diagnosis. Mental and physical exercise, and avoiding obesity may decrease the risk of AD; however, evidence to support these recommendations is weak. There are no medications or supplements that have been shown to decrease risk. Affected people increasingly rely on others for assistance, often placing a burden on the caregiver. The pressures can include social, psychological, physical, and economic elements. Exercise programs may be beneficial with respect to activities of daily living and can potentially improve outcomes. Behavioral problems or psychosis due to dementia are often treated with antipsychotics, but this is not usually recommended, as there is little benefit with an increased risk of early death. No treatments stop or reverse its progression, though some may temporarily improve symptoms. The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for Alzheimer ‘s Disease. It establishes that it is not reasonable to any agent to be able to treat Alzheimer‘s Disease successfully. Therefore, an appropriate correction is required.
Claim 12 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Enablement for the scope of “an autoimmune disease” or “immune disease “ generally is not present. Formula I to be effective against inflammation generally are contrary to medical science. Immunoregulatory abnormality or Inflammation is a process which can take place in virtually any part of the body. There is a vast range of forms that it can take, and there are causes for the problem, and various biochemical pathways including the inhibition of SSAO that will reduce the levels of pro-inflammatory enzyme products (aldehydes, hydrogen peroxide and ammonia), while SE-CRT interactions are also selectively inhibited as described in the specification (see page 1). There is no common mechanism by which all, or even most, inflammations arise. Mediators include bradykinin, serotonin, C3a, C5a, histamine, assorted leukotrienes and cytokines, and many, many others. Accordingly, treatments for inflammation are normally tailored to the particular type of inflammation present, as there is no, and there can be no “magic bullet” against inflammation generally.
Inflammation is the reaction of vascularized tissue to local injury; it is the name given to the stereotyped ways tissues respond to noxious stimuli. These occur in two fundamentally different types. Acute inflammation is the response to recent or continuing injury. The principal features are dilatation and leaking of vessels, and recruitment of circulating neutrophils. Chronic inflammation or "late-phase inflammation" is a response to prolonged problems, orchestrated by T-helper lymphocytes. It may feature recruitment and activation of T- and B-lymphocytes, macrophages, eosinophils, and/or fibroblasts. The hallmark of chronic inflammation is infiltration of tissue with mononuclear inflammatory cells. Granulomas are seen in certain chronic inflammation situations. They are clusters of macrophages which have stuck tightly together, typically to wall something off. Granulomas can form with foreign bodies such as aspirated food, toxocara, silicone injections, and splinters.
Otitis media is an inflammation of the lining of the middle ear and is commonly caused by Streptococcus pneumoniae and Haemophilus influenzae. Cystitis is an inflammation of the bladder, usually caused by bacteria. Blepharitis is a chronic inflammation of the eyelids that is caused by a staphylococcus. Dacryocystitis is inflammation of the tear sac, and usually occurs after a long-term obstruction of the nasolacrimal duct and is caused by staphylococci or streptococci. Preseptal cellulitis is inflammation of the tissues around the eye, and Orbital cellulitis is an inflammatory process involving the layer of tissue that separates the eye itself from the eyelid. These life-threatening infections usually arise from staphylococcus. Hence, these types of inflammations are treated with antibiotics.
Certain types of anti-inflammatory agents, such as non-steroidal anti-inflammatory medications (Ibuprofen and naproxen) along with muscle relaxants can be used in the non-bacterial cases. The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for inflammation. It establishes that it is not reasonable to any agent to be able to treat inflammation generally. Therefore, an appropriate correction is required.
Also, enablement for the scope of “an autoimmune disease “ or “ immune disease” generally is not present. Formula I to be effective against autoimmune disease generally are contrary to medical science The autoimmune disorder is a condition arising from an abnormal immune response to a normal body part There are at least 80 types of autoimmune diseases. Nearly any body part can be involved. Common symptoms include low grade fever and feeling tired. Often symptoms come and go.
The cause is generally unknown. Some autoimmune diseases such as lupus run in families, and certain cases may be triggered by infections or other environmental factors. Some common diseases that are generally considered autoimmune include celiac disease, diabetes mellitus type 1, Graves' disease, inflammatory bowel disease, multiple sclerosis, psoriasis, rheumatoid arthritis, and systemic lupus erythematosus.[1][4] The diagnosis can be difficult to determine.
Treatment depends on the type and severity of the condition. Nonsteroidal anti-inflammatory drugs (NSAIDs) and immunosuppressants are often used. Intravenous immunoglobulin may also occasionally be used. While treatment usually improves symptoms, they do not typically cure the disease.
About 24 million (7%) people in the United States are affected by an autoimmune disease. Women are more commonly affected than men.[1] Often they start during adulthood.[1] The first autoimmune diseases were described in the early 1900s.
The human immune system typically produces both T cells and B cells that are capable of being reactive with self-antigens, but these self-reactive cells are usually either killed prior to becoming active within the immune system, placed into a state of anergy (silently removed from their role within the immune system due to over-activation), or removed from their role within the immune system by regulatory cells. When any one of these mechanisms fail, it is possible to have a reservoir of self-reactive cells that become functional within the immune system. The mechanisms of preventing self-reactive T cells from being created takes place through negative selection process within the thymus as the T cell is developing into a mature immune cell.
Some infections, such as Campylobacter jejuni, have antigens that are similar (but not identical) to our own self-molecules. In this case, a normal immune response to C. jejuni can result in the production of antibodies that also react to a lesser degree with gangliosides of myelin sheath surrounding peripheral nerves' axons (i.e., Guillain–Barré). A major understanding of the underlying pathophysiology of autoimmune diseases has been the application of genome wide association scans that have identified a degree of genetic sharing among the autoimmune diseases.
Autoimmunity, on the other hand, is the presence of self-reactive immune response (e.g., auto-antibodies, self-reactive T cells), with or without damage or pathology resulting from it. This may be restricted to certain organs (e.g. in autoimmune thyroiditis) or involve a particular tissue in different places (e.g. Goodpasture's disease which may affect the basement membrane in both the lung and the kidney).
For a disease to be regarded as an autoimmune disease it needs to answer to Witebsky's postulates (first formulated by Ernest Witebsky and colleagues in 1957 and modified in 1994):
Direct evidence from transfer of disease-causing antibody or disease-causing T lymphocyte white blood cells
Indirect evidence based on reproduction of the autoimmune disease in experimental animals
Circumstantial evidence from clinical clues
Genetic evidence suggesting "clustering" with other autoimmune diseases
Autoimmune diseases have a wide variety of different effects. They do tend to have one of three characteristic pathological effects which characterize them as autoimmune diseases:
Damage to or destruction of tissues
Altered organ growth
Altered organ function
It has been estimated that autoimmune diseases are among the leading causes of death among women in the United States in all age groups up to 65 years.
A substantial minority of the population suffers from these diseases, which are often chronic, debilitating, and life-threatening
There are more than 80 illnesses caused by autoimmunity. The above list is by no means complete, but demonstrates the extraordinary breadth of causes, mechanisms and treatment (or lack thereof) for any immune or autoimmune disorder. It establishes that it is not reasonable to any agent to be able to treat any immune or autoimmune disorder generally. Therefore, an appropriate correction is required.
Claim 11 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention. The specification is not enabled for the treatment of
a disease related to the activity or expression of JAK kinase in a subject in need
comprising an effective amount of the compound or the stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof claim 1.
The claim is not directed to the treatment of the specific diseases, but the treatment of all kinds of diseases by using the mechanistic nature of treating or inhibiting the activity or expression of JAK kinase in a subject.
The specification falls short because data essential for treating numerous diseases by administering a therapeutically effective amount of the claimed compound to a person in need is not described in the specification.
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 claim 11 is
11. A method for treating or preventing a disease related to the activity or expression of JAK kinase in a subject in need thereof, the method comprising administrating to the subject an effective amount of the compound or the stereoisomer or optical isomer, pharmaceutically acceptable salt, prodrug or solvate thereof of any one of claims1
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 method of inhibiting the activity or expression of JAK kinase related to the disease in the human using the claimed compounds of formula I could result in the possibility of unpredictable effects Infections: As JAK inhibitors suppress the immune system, patients have an increased risk of common infections, such as upper respiratory tract infections (e.g., the common cold), urinary tract infections, and nasopharyngitis.
Herpes zoster (shingles): Reactivation of the herpes zoster virus is a commonly reported side effect across various diseases treated with JAK inhibitors. Vaccination is often recommended before starting therapy.
Gastrointestinal issues: Common gastrointestinal side effects include nausea and diarrhea. In some patients, severe cases of gastrointestinal perforation have been reported, particularly with higher doses of tofacitinib.
Headache: Headaches are a frequently reported adverse event.
Acne: The development of acne is another common side effect, especially for those being treated for atopic dermatitis.
Hyperlipidemia: Elevated levels of cholesterol and other lipids are a documented side effect, though it is not yet clear if this increases the risk of heart problems.
Cytopenias: Since JAK2 is involved in hematopoiesis, its inhibition can lead to cytopenias like anemia and neutropenia.
Hence, in the absence of a showing of correlation between all the well-known diseases claimed as capable of treatment by inhibiting the nhibiting the activity or expression of JAK kinase related to the disease in the patient with the claimed compounds of formula I and all the known diseases, one of skill in the art is unable to fully predict possible results from the administration of the claimed compounds of formula I due to the unpredictability of the role of treating any known diseases by inhibiting the activity or expression of JAK kinase in the patient with the claimed compounds in spite of a fact that the inhibiting the activity or expression of JAK kinase related to the disease can act as a potential target to treat others related diseases, i.e. whether promotion or inhibition would be beneficial for the treatment of all the diseases.
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 instant specification is that the compounds of formula I can be used to treat the list of diseases in the followings:
cancer, myeloproliferative disease, inflammation, immune disease, organ transplantation, viral disease, cardiovascular disease or metabolic disease, human or animal autoimmune disease, rheumatoid arthritis, skin disease, multiple sclerosis, rheumatoid arthritis, psoriatic arthritis, inflammatory bowel disease, myasthenia gravis, and psoriasis.
However, the specification is silent and fails to provide guidance as to whether all those diseases require the mechanistic nature of inhibiting or treating a disease related to the activity or expression of JAK kinase in the patient with the claimed compounds of formula I, i.e. the specification fails to provide a correlation between all those diseases and the inhibition of a disease related to the activity or expression of JAK kinase in the patient. Also, there is no direction and guidance for how all those diseases would be cured by using the claimed compounds of formula I.
The presence or absence of working examples
There is no working example for all the diseases-treatment by using the mechanistic nature of inhibiting or treating a disease related to the activity or expression of JAK kinase in the patient with the compounds of formula I except for the examples of biological test which exhibits very excellent activity of inhibiting JAK, especially against JAK1 and an excellent JAK1 selectivity. But the compounds which are disclosed in the specification have no other pharmacological data regarding the treatment of all those diseases using the claimed compounds. Also, the specification fails to provide sufficient working examples as to how those listed diseases can be treated by inhibiting the activity or expression of JAK kinase related to the disease in the patient with the compounds of formula I, i.e. again, there is no direct correlation between the listed diseases and the claimed compounds.
The breadth of the claims
The breadth of the claim is that the compounds of formula I can be used to treat all the known diseases mentioned in the above, without regards as to the side-effect of the claimed compounds on the stated diseases.
The quantity of experimentation needed
The quantity of experimentation needed is undue experimentation. One of skill in the art would need to determine which kinds of those diseases would be benefited by the affect of the claimed compounds and would furthermore then have to determine whether the claimed compounds would provide treatment of all the known diseases listed in the above.
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 which compounds exhibit the desired pharmacological activity and which diseases would benefit from this activity.
Thus, the specification fails to provide sufficient support of the broad use of the compounds of formula I for all kinds of diseases-treatment. As a result, necessitating one of skill to perform an exhaustive search for which all the known diseases can be treated by the compounds of formula I 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 which diseases can be treated by the compounds encompassed in the instant claims, with no assurance of success.
Conclusion
Claims 1-12 are rejected.
Claim 12 is objected.
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/TAYLOR V OH/Primary Examiner, Art Unit 1625 10/18/2025