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 .
DETAILED ACTION
Claims 1-4, 6-7, 9, 11-12, 27-28, 33-35, 39, 44, 50-52 and 59 are pending and are under consideration in the instant office action.
Priority
This application is a U.S. National phase application under 35 U.S.C 371 of PCT application PCT/US2022/016186, filed 02/11/2024 which claims priority under 35 U.S.C 119 (e) from provisional application serial No. 63148865, filed 2/12/2021.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 1-4, 6-7, 9, 11-12, 27-28, 33-35, 39, 44 and 50 are rejected under 35 U.S.C. 112, first paragraph, , because the specification, while being enabling for the specific compounds, compound no 1-106 recited in instant claim 44, does not reasonably provide enablement for all the compounds encompassed by the formula recited in instant claims encompassed by formula (I) or (II) or (IIa)
The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention and Breadth of claims:
As stated in MPEP 2164.05(a), “[t]he initial inquiry” for determining whether the Specification is enabling “is into the nature of the invention, i.e., the subject matter to which the claimed invention pertains.” In the instant case, the claimed invention pertains to compounds of Formula (I), which allegedly effective in modulation of FGF activity.
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First with regards to the formula recited in instant claim 1, it encompasses a large number of possible structural components for each variable of the compound of formula recited in instant claim 1.. The formula contains R groups which include heterocycle, heteroalkyl, alkyl, alkoxy, hydroxyl, aroxy and acyloxy. 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 rings, ring systems covered by the claims' scope along with varying choices for remaining variables. Further, applicants have not demonstrated that n in the cyclic substituents range from 1-16 result in effective compounds and there is no evidence of record that such compounds biological activity would be relevant.
The claims encompass optional substitutions of the variables without defining the substituents, which can therefore encompass substituents of varied structures and properties including nucleotides or peptides. The claims encompass a plethora of structurally divergent compounds and there is no evidence of record that the broad scope of the claimed compounds have the biological activity asserted by the applicants which is also very broad that is to treat any disease or injury in the subject.
While a subset of compounds encompassed by the instant formula are recited in instant disclosure and instant claim 44, it is noted that the following hypothetical compound is also encompassed by the instant claims.
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The State and Predictaility in the art, and relative skill of those in the art:
“[t]he state of the prior art is what one skilled in the art would have known, at the time the application was filed, about the subject matter to which the claimed invention pertains” and, as stated in MPEP 2164.05(b), “[t]he relative skill of those in the art refers to the skill of those in the art in relation to the subject matter to which the claimed invention pertains at the time the application was filed.” As discussed above, the instantly claimed invention pertains to method of treating bacterial infection with compounds of formula I which are alleged by the Specification to be useful for that purpose. At the time the instant application was filed, it would have been known by those of ordinary skill in the art that due in large part to the strict requirement of complementarity between a compound and its corresponding binding site on a target receptor or enzyme - compounds, in the vast majority of cases, demonstrate a remarkably high correlation between their structure, specificity and ability to produce a pharmacological effect. At the same time, it would have also been generally assumed that two compounds with similar chemical properties would exhibit similar biological effects. Thus, given a series of compounds that are shown to exert an activity of interest (or given a target of interest), the ordinarily skilled artisan would have expected that a limited genus of related compounds (e.g., compounds exhibiting near equal molecular shapes and volumes, approximately the same distribution of electrons, and similar physical properties such as hydrophobicity, etc.) would interact with the given target to elicit a related biological response. The relative skill of those in the art is high, generally that of an M.D. or Ph.D That factor is outweighed, however, by the unpredictable nature of the art. 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, 166 USPQ 18, at 24 (In cases involving unpredictable factors, such as most chemical reactions and physiological activity, the scope of enablement obviously varies inversely with the degree of unpredictability of the factors involved.), Nationwide Chemical Corporation, et al. v. Wright, et al., 192 USPQ 95 (one skilled in chemical and biological arts cannot always reasonably predict how different chemical compounds and elements might behave under varying circumstances), Ex parte Sudilovsky 21 USPQ 2d 1702 (Appellant's invention concerns pharmaceutical activity. Because there is no evidence of record of analogous activity for similar compounds, the art is relatively unpredictable).
Once a compound has been identified by ligand based and/or structure based drug design methods as potentially binding to the target molecule, it must be evaluated. However, as discussed by Anderson (Chem and Biol 10:787-797, 2003), “it is important to consider that the ranking assigned by the scoring function is not always indicative of a true binding constant, since the model of the target:ligand interaction is inherently an approximation. Usually, several molecules which scored well during the docking run are evaluated in further tests since even the top scoring molecule could fail in vitro assays… Finally, leads are brought into the wet lab for biochemical evaluation” (Page 794, Column 1). By that point, as noted by Thiel (Nature Biotechnol 2:513-519, 2004), “libraries are small and hit rates are on the order of one in ten” (Page 517, Column 2). This low level of predictability is not surprising considering that even minor structural changes can, and frequently will, drastically alter or eradicate a parent compound’s ability to modulate the activity of a specific receptor or enzyme. Indeed, modifying even a single atom in a compound can dramatically change the compound’s overall structure and - even though complementarity in one portion of the compound might be improved by the chemical revision - the overall binding or activity might be severely compromised.
The skilled artisan would view the synthesis of every possible variation of the compounds encompassed by formula as requiring much experimentation. In addition, the basis of the activity of the instantly claimed compounds as claimed is by its ability to increase activity of FGF-2. As such the ability of any of the encompassed compounds to effectively activity of FGF-2 as claimed resulting in therapeutic utility is highly unpredictable and requires undue amount of experimentation.
Amount of guidance/Existence of working examples:
As stated above, the compounds made are not representative of the instant scope but are closer to each other than to remaining scope. The instant specification discloses the preparation of several compounds (Compounds 1-106 as shown in Table 1, pages 5-19) of the instant specification, but the formula(I), (II) and (IIa) encompasses thousands of compounds that the instant specification is not enabled for.
There is no data shown with other compounds encompassed by the structure of claim1 such as where in R1 and R2 are C8-C16 aryl or or C8-C20 cycloalkenyl.and more.
Absence of working examples is a critical factor to be considered, especially in a case involving an unpredictable and undeveloped art. See MPEP 2164.
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, one of skill in the art would not accept the assertion that a majority of the compounds encompassed by the claims can be prepared and also be effective as FGF-2 enhancers.. As such, the only way to ascertain which of the hundreds of claimed compounds encompassed by Formula (I) are usable based on the limited disclosure would require undue experimentation. That is, the only way one skilled in the art is enabled to use the entire scope of the claim based on the instant disclosure entails undue experimentation.
To overcome this rejection, Applicant should narrow the scope of the claims such that they bear a reasonable correlation with the disclosure.
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).
Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112, first paragraph, since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no reasonable assurance of success.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 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 51-52 and 59 are rejected under 35 U.S.C. 112, first paragraph, , , because the specification, while being enabling for the treatment of stroke by treatment with Compound -2 , does not reasonably provide enablement for the treatment of any and every disease or injury or any of the diseases claimed in claims 51-52 and 59 with each and every compounds encompassed by the formula recited in instant claims encompassed by formula (I) 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 claims are directed to a method of treatment a subject having a disease or injury comprising administering to said subject a compound of formula (I) recited below. Accordingly the specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
Attention is directed to In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 where the court set forth the eight factors to consider when assessing if a disclosure would have required undue experimentation. Citing Ex parte Forman, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors: (1) the nature of the invention; (2) the state of the prior art; (3) the relative skill of those in the art; (4) the predictability or unpredictability of the art; (5) the breadth of the claims; (6) the amount of direction or guidance presented; (7) the presence or absence of working examples; and (8) the quantity of experimentation necessary.
All of the Wands factors have been considered with regard to the instant claims, with the most relevant factors discussed below.
Nature of the invention:
The invention is drawn to method of treating a subject having a disease or injury comprising administering to said subject a therapeutically effective amount of the pharmaceutical composition of comprising the following compounds of formula (I) shown below
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Breadth of the claims
The breadth of the claims is extensive. The claims relate to an extremely large number of possible compounds as recited in the 112 rejection of claim 1 above , which are all supposed to be effective in the treatment of any of the diseases or any injury known. The different diseases claimed in claim 52 and 59 have different pathologies, symptoms, etiology and, if not all most of these disorders are difficult, and often impossible to predict, prevent and treat. In addition the number of compounds encompassed by the formula (I) is also extremely vast since they encompass a large number of possible structural components for each variable of the compound of formula (as noted in the 112 rejection above).
Relative skill of those in the art
The relative skill of those in the art is high.
State of the prior art/Predictability or unpredictability of the art:
The state of the prior art is such that it involves screening both in vitro and in vivo to determine which compounds exhibit the desired pharmacological activities (i.e. which compounds treat which specific disease). 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 instant claimed invention is highly unpredictable as discussed below:
The present claims relate to the mechanism underlying the treatment of the claimed diseased with the compounds of the instant invention which is the ability of the compounds to enhance FGF-2 activity. Although the discovery of such a mechanism may be an important piece of scientific knowledge, it still needs to be turned into a practical application in the form of a specified actual treatment of the pathological conditions.
It is noted that the pharmaceutical art is unpredictable, requiring each embodiment to be individually assessed for physiological activity. For instance, drugs that are used to treat the central nervous system (CNS) face several hurdles. First of all, the drug needs to be able to reach the site of action. There are several natural barriers to drug penetration into the CNS including physical impediments, such as the blood-brain barrier and blood-cerebral spinal fluid barrier, in addition to the presence of drug specific transporters in the cells comprising these barriers. A drug intended for the CNS must cross the blood-brain barrier either via passive diffusion or receptor-mediated transport. Typically the more lipid-soluble a drug, the easier it is for it to successfully penetrate the physical barriers present in the CNS. Nature has put in place a formidable set of barriers to prevent drug penetration into the CNS. Agents targeting neurodegenerative diseases such as dementia, psychoses, phobias, depression etc must overcome them in order to be effective. In re Fisher, 427 F.2d 833, 166 USPQ 18 (CCPA 1970) indicates that the more unpredictable an area, the more specific enablement is necessary in order to satisfy the statute. In the instant case, the claimed invention is highly unpredictable since one skilled in the art would recognize that in regards to therapeutic effects any and every diseases or any injury, whether or not the disease is effected by all the compounds set forth in the invention and more importantly, if the encompassed compounds can even penetrate the blood-brain barrier, would make a difference.
Additionally, there is no common mechanism by which all the claimed diseases known or the ones recited in claim 51 and 59 arise. Accordingly, treatments for these diseases are normally tailored to the particular type of disease as there is no, and there can be no “magic bullet” against all the known conditions or the other claimed diseases in general. The pathogenesis of each of these diseases is complex and different. The varied anatomic specificities of each of the disease need to be considered, it is very difficult to treat the disease without knowing its full scope of etiology and molecular mechanisms. . The diseases claimed to be treated by the compounds of the instant application has variable pathologies and each one of them is characterized by modulation of several different pathways. For example in a condition such as phobias or anxiety Sahley (Social anxiety and phobia, Pain and Stress publication, 2001, pages 1-3 ) teaches that people with social anxiety and phobia have a low serotonin level and an overactive limbic system that be controlled by the amino acids GABA, glutamine, glycine and 5HTP. Sahley teaches that drugs only block the symptoms and the anxiety and panic will return as soon as the drugs are stopped (page 1, right col.). Sahley also teaches that there is no magic bullet which takes away anxiety and phobias overnight and the treatment involves treating directly with neurotransmitters in addition to other lifestyle changes (page 2, right col). The treatment of these disorders in general is complicated. In case of Parkinson’s’ disease (PD) the pathways involved in the manifestation of this disease is extremely complicated (see page R 189, in Thomas et al, Human Molecular Genetics, 2007, Vol.16, review issue 2, R183-R194). Parkinson’s disease (PD) is a complex disease with multiple etiological factors involved in the disease pathogenesis and there are several different pathways that are important in modulating pathogenic events leading to the death of dopaminergic neurons in PD (Thomas et al.) . As such inhibition of one of the minor pathway in the PD disease process may or may not produce positive therapeutic results absent any direct evidence clinically of their activity.
Additionally, in terms of all the compounds encompassed by formula (I) and ordinarily skilled artisan would view that the synthesis of all possible variations of the compounds of formula (I) would require much experimentation let alone testing all the compounds for clinical efficacy against all the different diseases claimed.
Amount of guidance/Existence of working examples:
More importantly, there is only one examples showing just one compound (compound 2) for only one condition of disease (Stroke) present in the specification. Instant specification while they do show the enhancement of FGF-2/FGFR1 complex with 18 of the compounds which falls under the broad compound formula (I), in terms of activity against the claimed diseases, they only show the testing of just one compound , compound 2 in an in-vivo assay to test for stroke recover (Example 4)). Even if the enhancement of the FGF-2 supposedly exhibited by the 18 compounds of formula (I) is indisputably a pharmacological effect, it cannot in itself be considered a therapeutic application, nor can it fully enable the treatment of any and every disease or injury known in the art and the specific conditions listed in claims 51 and 59. Applicants fail to provide any in-vitro or in-vivo or clinical data to verify the therapeutic activity of a representative number of these compounds in the various diseases claimed. As such applicant fails to provide a clear indication for the use of their claimed compounds in the treatment of various diseases claimed.
Thus, the specification fails to provide clear and convincing evidence in sufficient support for using the claimed compounds in a method to treat all the different disease as recited in the instant claims. Thus, factors such as “sufficient working examples”, “the level of skill in the art”, and “predictability”, etc. have been demonstrated to be sufficiently lacking in the instant claimed methods. In view of the breadth of the claims, the chemical nature of the invention, and the lack of working examples regarding the activity of the claimed compound, one having ordinary skill in the art would have to undergo an undue amount of experimentation to use the invention commensurate with the scope of the claims.
Genetech, 108 F.3d at 1366, 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 discussed above, to practice the claimed invention herein, a person of ordinary skill in the art would have to engage in undue experimentation to test which diseases or which injuries can be treated by which compound encompasses in the instant claims, with no assurance of success. Thus, rejection of claims 51-22 and 59 under 35 U.S.C. §112, first paragraph, is deemed proper.
Conclusion
Claims 1-4, 6-7, 9, 11-12, 27-28, 33-35, 39, 44, 50-52 and 59 are rejected. No claims are allowed
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SAVITHA RAO whose telephone number is (571)270-5315. The examiner can normally be reached on Mon-Fri 7 am to 4 pm..
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SAVITHA M RAO/Primary Examiner, Art Unit 1691