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 1-13 are pending.
Claims 1-7 and 9-13 are rejected.
Claim 8 is allowable.
DETAILED ACTION
1. Claims 1-13 are under consideration in this Office Action.
Priority
2. It is noted that this application is a 371 of PCT/IB2023/000170 03/02/2023, which has a foreign priority document CHINA CN202210200094.1 03/02/2022,
Drawings
3. The drawings filed on 9/02/24 are accepted by the examiner.
IDS
4. The IDS filed on 10/02/24 & 12/8/25 are reviewed by the examiner.
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 1-6, 9-13 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.
In claims 1-6, the phrases “ W is selected from -(CH2)m or -NR6(CH2)m-“ ; “ X is selected from O or S”’; no and ni are each independently selected from 1, 2 or 3”; “ m is selected from 0, 1, 2, 3, 4, 5 or 6” ; “ Ro is selected from -NR'R", -O(CH2)mNR'R", substituted or unsubstituted 5-8 membered heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl; “ each independently selected from C1.6 alkyl,… or heteroaryl “; “ R' and R" are each independently selected from hydrogen,…. or C1.6 alkoxyamide” ; “R1 and R6 are each independently selected from hydrogen, or -S(0)2- alkyl”; “ R2, R3, R4, and R5 are each independently selected from hydrogen, …, or C1.6 alkylsulfoxide”; “R7 and R8 are each independently selected from hydrogen,…, or 3-8 membered heteroaryl”;; m is selected from 0, 1, 2, 3, 4, 5 or 6; RO is selected from -NR'R", -O(CH2)mNR'R", substituted or unsubstituted 5-8 membered heterocyclyl, substituted or unsubstituted 5-8 membered heteroaryl; “ “ m is selected from 1 or 2”: “ R1 is selected from hydrogen, or -S(0)2- alkyl”; ““ R2, R3, R4, R5and R6 are each independently selected from hydrogen, …, or C1.6 alkylamino”;” at least one heteroatom selected from N, O or S” are recited. These expressions are improper because the Markush expression would require a close ended “and “ instead of an open ended “or” at the end. Appropriate correction is required.
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 7 is 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 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 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 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 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.
h) The breadth of the claims includes all of the hundreds of thousands of compounds of formula *** 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 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 10-13 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 a disease or disorder associated with histamine H3 receptor in a subject,. 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 the disease or disorder associated with histamine H3 receptor. The only established prophylactics are vaccines not an antagonist compound 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 chronic and acute pain occurs. This would require extensive and potentially opened ended clinical research on healthy subjects. 2) The passages from a paragraph#45 on page 17 to a paragraph#0048 on page 18 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 preventive medicine for a disease or disorder associated with histamine H3 receptor in a subject 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 getting a disease or disorder associated with histamine H3 receptor in a subject before the fact. 6) The artisan using Applicants invention would be a Board Certified physician in a disease or disorder associated with histamine H3 receptor with an MD degree and several years of experience. Despite intensive efforts, pharmaceutical science has been unable to find a way of getting a composition to be effective for the prevention of any disease or disorder associated with histamine H3 receptor 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 any disease or disorder associated with histamine H3 receptor generally. That is, the skill is so low that no composition effective generally against any cancers 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 of antagonists.
The Examiner suggests deletion of the word “preventing” from the claim.
Claim 10 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 claim is not directed to the treatment of the specific diseases, but the method for treating a disease or disorder associated with histamine H3 receptor in a subject, comprising administration of a therapeutically effective amount of an antagonist of claim 1.
The specification falls short because data essential for numerous diseases or disorders associated with histamine H3 receptor in a subject 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 current claim 10 is recited in the following:
A method for preventing or treating a disease or disorder associated with histamine H3 receptor in a subject, comprising administration of a therapeutically effective amount of an antagonist of claim 1 or a pharmaceutically acceptable salt thereof, to the subject in need of.
The state of the prior art
Nirogi et al (WO 2012/114348 A1) discloses compounds and a method of treating cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep· apnea, obesity, eating disorders and pain, comprising administering to a patient in need thereof an effective amount of a compound or pharmaceutically acceptable salt thereof according to any one of claims 1 to 3.
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However, there are no conclusive data which allow the approval for treating all kinds of diseases or disorders associated with histamine H3 receptor in a subject
by administration of a therapeutically effective amount of an antagonist of claim 1 or a pharmaceutically acceptable salt thereof, to the subject.
The amount of direction or guidance present
The direction present in the current specification is that the claimed therapeutically effective amount of an antagonist of claim 1 can be used to treat various diseases or diseases or disorders associated with histamine H3 receptor in a subject which include
cognitive disorders, dementia, attention deficit hyperactivity disorder, schizophrenia, epilepsy, sleep disorders, sleep apnea, obesity, eating disorders, pain and pruritus, neuropathic pain, including but not limited to peripheral neuropathic pain or central neuropathic pain, trigeminal neuralgia, glossopharyngeal neuralgia, acute or chronic inflammatory demyelinating polyneuropathic neuralgia, alcoholic polyneuralgia, chemotherapy-induced polyneuropathic neuralgia, complex regional pain syndrome, embedded compression neuralgia (e.g., carpal tunnel syndrome), HIV sensory neuralgia, medically induced neuralgia (e.g., post-mastectomy pain), tumor compression or infiltration neuralgia, nutritional deficiency-associated neuralgia, diabetic neuralgia, phantom limb pain, postherpetic neuralgia, post-radiation plexopathy, radiculopathy (cervical, thoracic, or lumbosacral), toxic exposure-associated neuralgia, or post-traumatic neuralgia, post-stroke pain, multiple sclerosis-associated pain, Parkinson's disease-associated pain, post-traumatic spinal cord injurious pain, spinal cord cavernous disease, post ischemic myelopathy, compressive myelopathy, HIV myelopathy, or post-radiation myelopathy.
However, the specification is silent and fails to provide guidance as to whether all those diseases require the mechanistic nature of using an antagonists of claim 1 in the patient with the claimed compounds, i.e. the specification fails to provide a correlation between all those diseases and the antagonist of the claim 1 in the patient. Also, there is no direction and guidance for how all those diseases would be cured by using the claimed antagonists in the claim 1.
The presence or absence of working examples
There are some examples such as the antagonistic of compounds target to Histamine H3 receptor, the analgesic effects of compounds BIOS-B-12 and BIOS-B-14, antipruritic ability of compounds BIOS-12 and BIOS-18 without any actual data for treating those various diseases mentioned in the above. Thus, the specification fails to provide sufficient working examples as to how those diseases can be treated by using the antagonists in the claim 1 in the patient, i.e. again, there is no direct correlation between the diseases and the claimed compounds directly.
The breadth of the claims
The breadth of the claim is that the claimed antagonistic compounds in the claim 1 can be used to treat all the above known diseases which can be benefited by the antagonistic action of the claimed compounds 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 disorders would be benefited by the antagonistic effect of the claimed compounds and would furthermore then have to determine whether or not 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 theart 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 antagonists of the claimed 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 claimed antagonists of the claimed compounds 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 all kinds of the claimed compounds 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 claimed compounds encompassed in the instant claims, with no assurance of success.
Conclusion
Claims 1-7 and 9-13 are rejected.
Claim 8 is allowable.
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 9/2/2026
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