DETAILED ACTION
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 . 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 (i.e., changing from AIA to pre-AIA ) 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.
Priority
The instant application is a 371 of PCT/KR2022/004147 filed on 03/24/2022 and claims foreign priority to Korea application no. KR10-2021-0039963 filed on 03/26/2021. The certified copy of the foreign priority application filed on 09/22/2023 is acknowledged.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 09/22/2023 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Status of the Claims
The preliminary claim amendments filed on 09/22/2023 is acknowledged. Claim 5 is amended.
Accordingly, claims 1-6 are pending and being examined on the merits herein.
Claim Objections
Claims 1, 3, and 6 are objected to because of the following informalities:
Claims 1 and 3 recites “… thereof.” followed by the recited Formulas and a parenthetical, and Claim 6 recites “… Reaction Scheme 2.” followed by the recited reaction schemes and a parenthetical.
MPEP 608.01(m) recites “Each claim begins with a capital letter and ends with a period. Periods may not be used elsewhere in the claims except for abbreviations.”. Therefore, the period should be moved to the end. Furthermore, the parentheses for each of these claims should be removed for clarity.
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.
Claim 2 is 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 applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites “the heteroaryl”, “the aryl”, and “the alkyl”.
There is insufficient antecedent basis for these limitations in the claim because claim 1 (claim 2 depends from claim 1) recites a heteroaryl and alkyl twice “Y and Z are … heteroaryl … R is … alkyl … when Y or Z is substituted, Y or Z is optionally … alkyl … heteroaryl”, and also recites aryl three times “Y and Z are … aryl … R is … aryl … when Y or Z is substituted, Y or Z is optionally … aryl”, making it unclear which groups are being further limited in claim 2.
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 5 is 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 treating A2A or A3 adenosine receptor-related diseases, does not reasonably provide enablement for preventing A2A or A3 adenosine receptor-related diseases. 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.
To be enabling, the specification of the patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fed. Cir. 1993). Explaining what is meant by “undue experimentation,” the Federal Circuit has stated:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which the experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996).
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth by 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 Formal, 230 USPQ 546 (BdApls 1986) at 547 the court recited eight factors:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples, and
8) The quantity of experimentation necessary
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention, the breadth of the claims, and relative skill level
The invention relates to a pharmaceutical composition for preventing or treating A2A or A3 adenosine receptor-related diseases, comprising the adenosine derivative of according to instant claim 1.
The claims are broad in that they encompass prevention of any A2A or A3 adenosine receptor-related diseases.
In the absence of an explicit definition in Applicant’s specification, the claims are given their broadest reasonable interpretation (See MPEP 2111). Institute for International Medical Education (IIME, reference included with PTO-892), defines “prevention” as promoting health, preserving health, and to restore health when it is impaired, and to minimize suffering and distress (see page 16, “Prevention”). IIME further states that “Primary prevention refers to the protection of health by personal and community wide effects, such as preserving good nutritional status, physical fitness, and emotional well-being, immunizing against infectious diseases, and making the environment safe. Secondary prevention can be defined as the measures available to individuals and populations for the early detection and prompt and effective intervention to correct departures from good health. Tertiary prevention consists of the measures available to reduce or eliminate long-term”.
Therefore, in order to give the broadest reasonable interpretation to the claims, “prevention” or "prevent" are thus interpreted to mean that the onset of a condition never occurs and the patient’s health is protected and preserved.
The relative skill of those in the art is high, that of an MD or PHD, someone with experience in the recited diseases.
The amount of direction or guidance provided and the presence or absence of working examples
Applicant demonstrates in pages 170-171 the evaluation of binding affinity for adenosine receptor for the claimed compounds. Applicant lists in Table 2 on page 170 that the compounds exhibited high binding affinity for human adenosine A2A and A3 receptors and generally low affinity for A1 and A2b receptors. Applicant further states that it can be expected that the adenosine derivative compounds can regulate the activity of A2A or A3 receptor, and thus can be effective for treatment of various brain, cardiovascular, sleep, inflammation, and immune system diseases and the like in which the receptors are involved.
However, the instant disclosure does not identify a method that could be used by one of ordinary skill in the art to determine that a subject would have predictably developed A2A or A3 adenosine receptor-related diseases without the claimed methods in order to establish that the recited diseases was prevented.
The described example suggests that the recited compounds were effective in regulating the activity of A2A or A3 receptors. However, the example does not demonstrate prevention of the recited diseases or a predictable method to identify patients who would have developed the recited diseases.
The state and predictability of the art
There are no art recognized methods that could be used to establish that A2A or A3 adenosine receptor-related diseases was prevented using therapeutic treatment or to identify patients who would predictably develop the recited diseases in order to predictably identify that prevention was achieved using therapeutic approaches. Rather, the art indicates that the recited diseases were not predictable.
Carpenter (in PTO-892) teaches adenosine receptors (AR) including A1, A2A, A2B, and A3 as potential therapeutic targets in a variety of pathophysiological conditions, including sleep disorders, cancer, and dementia, which has made them important targets for structural biology (see Abstract and second paragraph left column page 2). However, Carpenter teaches that one of the challenges of therapeutic intervention has been targeting individual AR subtypes with sufficient specificity to limit off-target side effects (see second paragraph left column page 2). Carpenter teaches that improvements in subtype specificity, coupled with the development of allosteric modulators that bind outside the orthosteric site, and biased ligands that can target a distinct signaling pathway associated with an individual AR subtype, may help to eliminate side effects entirely and further teaches that structure-based drug design, which involves in silico screening of vast compound libraries against experimentally determined receptor structures, offers huge potential for the development of a new generation of highly selective orthosteric, allosteric, and biased ligands, however, the difficulty of crystallizing G
protein-coupled receptors (GPCRs) has, until recently, hindered this approach (see second paragraph left column page 2 to first paragraph right column page 2). Carpenter teaches that structural determination of GPCRs such as AR are notoriously challenging due to their conformationally dynamic nature and poor
thermostability when extracted from the plasma membrane, and further teaches that a variety of methods have been developed to provide insights into the structure of AR and ligand binding specificity (see second paragraph right column page 2).
The teachings of Carpenter demonstrates that prevention of A2A or A3 adenosine receptor-related diseases is not predictable due to challenges of therapeutic intervention to target individual AR subtypes with sufficient specificity to limit off-target side effects and the complexity/difficulties to characterize the structure of AR subtypes to better understand its ligand binding specificity. Therefore, the preventative application against A2A or A3 adenosine receptor-related diseases using the recited composition is highly unpredictable in the arts because there is no predictable way to determine that an A2A or A3 adenosine receptor-related disease can be prevented using the claimed method.
Morelli (in PTO-892) teaches that adenosine A2A receptors may be a viable target for the treatment of Parkinson’s disease (see Abstract). Morelli teaches that the drug treatment of Parkinson’s disease (PD) is accompanied by a loss of drug efficacy, the onset of motor complications, lack of effect on non-motor symptoms, and a failure to modify disease progression (see Abstract). Morelli teaches that A2A receptor compounds produce alterations in motor behavior, either alone or in combination with dopaminergic drugs, which suggest that they will be effective in the symptomatic treatment of PD (see Abstract). However, Morelli teaches that these effects have proven difficult to demonstrate on a consistent basis, and further clinical trials are required to establish the clinical utility of this drug class (see Abstract). Morelli further concludes that blockade of A2A receptors may produce adverse effects in regions other than the brain, such as the heart, kidney, lung and inflammatory responses in general (see section Conclusions on page 608). Therefore, Morelli teaches that more detailed studies should be undertaken in the future in both experimental animals and humans to clarify whether (and under which specific conditions) A2A receptor antagonists may be used as safe and effective agents in the treatment of Parkinson’s Disease (see section Conclusions on page 608).
The teachings of Morelli demonstrates that prevention of a A2A or A3 adenosine receptor-related disease such Parkinson’s Disease is not predictable due to difficulties in demonstrating the therapeutic effects on a consistent basis as well as potential adverse effects when blocking A2A receptors and more experimentation is needed to determine how these A2A receptor antagonists can be used safely and effectively for the treatment of Parkinson’s disease. Therefore, the preventative application against A2A or A3 adenosine receptor-related diseases using the recited composition is highly unpredictable in the arts because there is no predictable way to determine that an A2A or A3 adenosine receptor-related disease can be prevented using the claimed method.
The quantity of experimentation necessary
Because of the known unpredictability of the art, and in the absence of a predictable method to identify patients who would develop an A2A or A3 adenosine receptor-related disease without treatment, one of ordinary skilled in the art would not be able to predictably use the claimed agent to prevent the recited diseases. Furthermore, the quantity of experimentation to develop a method that could be used to prevent an A2A or A3 adenosine receptor-related diseases would be undue because a method to predictably identify a patient who would get the recited diseases does not exist and as described above, one of ordinary skill would have to further develop this method such that the recited method could then be used as a preventative measure against the recited diseases. Accordingly, the instant claims do not comply with the enablement requirement of §112, since to practice the invention claimed in the patent a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claim(s) 1-5 are rejected under 35 U.S.C. 103 as being unpatentable over KR20120103313 (in IDS filed 09/22/2023, an English translation is provided in PTO-892 and used as the basis for this rejection) in view of Tan et al. (Phytotherapy Research, 2021 (published online 10/08/2020) in PTO-892).
KR’313 teaches a pharmaceutical composition for treating an inflammatory disease comprising the compound of Formula 1 shown below (see Abstract):
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, wherein X is S or O, Y is CH2; or X and Y together form cyclopropyl; R1 is hydrogen, C4-8 alkyl, C4-8 alkenyl, or C4-8 alkynyl; R2 is hydrogen, C4-8 alkyl, C4-8 alkenyl, C4-8 alkynyl, or furanyl; and R3 is amine or C4-8 alkynyl (see paragraph 0010). KR’313 teaches the above compound may be useful for the treatment of inflammatory diseases (see Abstract). KR’313 teaches that their compounds have high binding affinity and selectivity as an A2A adenosine agonist (see fifth paragraph on page 2) as well as exhibiting anti-inflammatory activity (paragraph 0084). KR’313 teaches that A2A receptor agonists have been studies as antihypertensives, antipsychotics, antiarrhythmics, fat metabolism inhibitors (diabetes agents), and brain protectors (paragraph 005) as well as are known to inhibit oxidative species induced by physiological stimuli such as neutrophil chemoattractant, cytokines, and lipid products (paragraph 0006). KR’313 further teaches that various A2A and A3 agonists and antagonists have been applied as new therapeutics drugs for diseases such as asthma, heart diseases, Parkinson’s disease, and others (paragraphs 0005 and 0009).
KR’313 demonstrates a specific species of the Formula 1 compound shown below:
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The difference between KR’313 and the instant invention is that the KR’313 compound has a 3’OH group on the sugar, whereas the compound of the instant invention does not have the 3’OH group.
Tan teaches the use of cordycepin to exert protective effects against inflammatory injury for many diseases including acute lung injury (ALI), asthma, rheumatoid arthritis, Parkinson's disease (PD), hepatitis, athero-sclerosis, and atopic dermatitis (see Abstract). Tan teaches the structure of the cordycepin in Figure 1 and shown below:
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Tan further teaches that cordycepin is an A2A and A3AR agonist and can bring about anti-inflammatory effects by inhibiting the expression of the pro-inflammatory cytokines (see right column, page 1286). Tan teaches that cordycepin (3’-deoxyinosine) has limited oral bioavailability (see left column section first paragraph under section “Pharmacokinetic” on page 1292), and hence several modifications of cordycepin as shown in Figure 3 on page 1393 have been performed in order to increase its bioavailability (see left column first paragraph under section “Derivatives” on page 1292).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the compound of KR’313 by removing the 3’OH group as shown in Tan to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because Tan demonstrates a similar adenosine analog compound (cordycepin) with no 3’OH group that is also an effective A2A receptor agonist useful for treating the same inflammatory diseases, and further demonstrates similar modifications to the cordycepin structure. Therefore, an ordinary skilled artisan could have predictably considered modifying the structure of the KR’313 compound by removing the 3’OH position with a reasonable expectation of success.
In regards to instant claim 4, it would have also been prima facie obvious before the effective filing date of the claimed invention to have substituted the butyl group at the end of the alkyne with C5-C8 alkyl group as disclosed in KR’313 to arrive at the claimed invention. One of ordinary skill in the art would have made this modification with a reasonable expectation of success because KR’313 provides guidance of C4-8 alkynyl groups as alternatives suggesting analogous properties. Therefore, an ordinary skilled artisan could have predictably considered substituted the butyl group with a C5-8 alkyl chain with a reasonable expectation of success.
Claim(s) 6 is rejected under 35 U.S.C. 103 as being unpatentable over KR20120103313 (in IDS filed 09/22/2023, an English translation is provided in PTO-892 and used as the basis for this rejection) in view of Tan et al. (Phytotherapy Research, 2021 (published online 10/08/2020) in PTO-892), Dong et al. (CECNet, 2011 in PTO-892), and Wang et al. (Bioorganic and Medicinal Chemistry, 2004 in PTO-892), and as evidenced by Maiti et al. (Journal of Organic Chemistry, 1996 in PTO-892).
The teachings of KR’313 as described above.
Furthermore, KR’313 in Reaction Scheme 3 demonstrates the synthesis of their compounds by the conversion of the chlorine on the adenine base to NH3 by reacting with ammonia, which meets the limitation of recited step as well as the conversion of the Z position moiety by substituting an iodide group with a recited Z group, which meets the limitation of recited step (i) (shown below and page 3 under section “Reaction Scheme 3”):
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KR’313 in Reaction Scheme 2 demonstrates the conversion of the Y position moiety by substituting a bromine group with a recited Y group (shown below and page 3 under section “Reaction Scheme 3”):
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Here, KR’313 teaches the same recited step (l) to convert the iodide to a Z group as well as the recited step (m) to convert the chlorine to NH3 in the recited reaction scheme 2. However, KR’313 does not teach the recited step (i) to convert the iodide to a recited Y group, the recited step (k) to attach the tetrahydrofuran diacetate and to further convert the 2’OAc on the sugar to OH by reacting with NH3, and the recited step (j) to remove a THP (tetrahydropyran) protecting group with PPTS.
The teachings of Tan are as described above.
Dong teaches a convenient route for the synthesis of adenosine (see Abstract). Dong demonstrates in Fig 1. on page 2 the synthesis steps involved and shown below:
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Here, Dong also teaches the conversion of the chlorine group on the base to NH3 by reacting with NH3. Additionally, Dong teaches the sequence of attaching a tetrahydrofuran acetate to the adenine base and further deacetylating the OAc groups on the sugar by reacting with NH3.
Wang teaches the synthesis of 6-substitued purine and 9-beta-D-ribofuranosyl purine analogue compounds (see Abstract). Wang demonstrates in Scheme 1 on page 1426 the synthesis of 6-substitued purines and shown below:
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Here, Wang teaches and demonstrates the synthesis of the modified purine base by protecting the base with DHP (3,4-dihydro-2H-pyran) to form a THP (tetrahydropyran) protecting group and removing this group using acidic methanol (iii) in DCM (see right column last paragraph page 1425). Furthermore, as evidenced by Maiti, standard synthesis procedures of removing THP protecting groups can also be carried out using PPTS in CH2Cl2 (DCM).
It would have been prima facie obvious before the effective filing date of the claimed invention to have modified the Scheme 3 reaction disclosed in KR’313 by substituting an iodide group with a Y group as suggested in KR’313, substituting the sugar moiety in the reaction scheme of KR’313 with the 3’deoxy sugar of Tan by using the acetylated sugar attachment sequence steps shown in Dong, and further adding and removing a THP protecting group on the adenine base as disclosed in Wang before the attachment of the sugar to arrive at the claimed invention. One of ordinary skill would have made these modifications with a reasonable expectation of success because KR’313 demonstrates the substitution of a bromide with a recited Y group at the same position as well using iodide substitution at another position. So, an ordinary skilled artisan could have predictably considered iodide substitution in place of the bromide substitution with a reasonable expectation of success. Furthermore, Tan provides guidance of a similar adenosine compound that contains a sugar moiety without the 3’OH group useful for the same purpose as described above, and Dong provides guidance of a synthesis method for a similar adenosine compound by attaching a similar acetate sugar form to the adenine base and further reacting with NH3 to convert the OAc and Cl groups to OH and NH3, respectively. Therefore, an ordinary skilled artisan could have predictably considered modifying the reaction scheme of KR’313 by incorporating the 3’deoxy sugar moiety of Tan using the synthesis sequence steps of Dong by attaching the acetate sugar form to the adenine base and further reacting with NH3 with a reasonable expectation of success. Lastly, Wang demonstrates the synthesis of a similar modified purine base by protecting the base with a THP group at the same location and further removing the THP group after modification of the base. Therefore, an ordinary skilled artisan could have predictably considered attaching the THP protecting group before modification of the adenine base as disclosed in the combined teachings of KR’313, Tan, and Dong described above and could have removed the THP group using known standard procedures such as PPTS before attaching the sugar moiety as disclosed in the combined teachings of KR’313, Tan, and Dong described above with a reasonable expectation of success.
Even though the combination of the references described above do not necessarily teach the same sequence of steps, MPEP 2144.04 II C recites “… selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results …”. Therefore, the combined references described above teach all of the same steps of making the recited compound and would be prima facie obvious to select any order of these steps to arrive at the instant invention.
Conclusion
No claim is found allowable.
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/D.H.C./Examiner, Art Unit 1693
/SCARLETT Y GOON/Supervisory Patent Examiner, Art Unit 1693