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 .
Election/Restrictions
Applicant’s election without traverse of cyclophosphamide (CYP)-induced cystitis as the elected cystitis species, and 8-aminoguanine as the elected PNPase inhibitor species are maintained.
Status of Claims
Acknowledgement is made of the receipt and entry of the amendment to the claims filed on November 24, 2025, wherein claims 1, 5, 9 and 17 are amended; claims 2-4, 6-8, 10-12, 15-16, 19-50 and 53 are cancelled; claims 13-14, 18, 51-52 and 54-56 are unchanged.
Claims 1, 5, 9, 13-14, 17-18, 51-52 and 54-56 are under examination in accordance with the elected species.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on November 24, 2025 was filed after the mailing date of the Non-Final Office Action on August 26, 2025. The submission is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Priority
The instant application 17/434,894 filed on August 30, 2021 is a 371 of PCT/US2020/022697 filed on March 13, 2020, which claims priority to, and the benefits of U.S. Provisional Application No.
62/817,859 filed on March 13, 2019, and U.S. Provisional Application No. 62/877,220 filed on July 22, 2019.
Applicant’s claim for the benefit of a prior-filed application under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, 365(c), or 386(c) is acknowledged. Applicant has not complied with one or more conditions for receiving the benefit of an earlier filing date under 35 U.S.C. 119(e) as follows:
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994).
The disclosure of the prior-filed application, U.S. Provisional Application No. 62/817,859 and U.S. Provisional Application No. 62/817,859, fails to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. The prior-filed application fails to disclose cyclophosphamide (CYP)-induced cystitis, which is the elected cystitis species. Therefore, the priority date of claims 1-5, 9, 13-14, 17-18, 51-52, and 54-55, drawn to a method of treating cystitis, including cyclophosphamide (CYP)-induced cystitis, are determined to be March 13, 2020, which is the filling date of 371 of PCT/US2020/022697.
Action Summary
Applicant’s amendment to the claims overcome each and every objection previously sets forth in the Non-Final Office Action mailed on October 5, 2023 unless otherwise noted.
Acknowledgement is made of the receipt of the amendment to the specification filed on November 24, 2025; However, applicant’s amendment to the specification has not been entered, because said amendment does not use the latest specification filed on December 6, 2024 but uses the earliest filed specification on August 30, 2021.
Claims 1-5, 9, 13-14, 17-18, 51-52, and 54-56 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 are maintained, but revisited and modified in view of the claim amendments.
Claims 1-4, 9, 13-14, 17-18, 51-52 and 54-55 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 are maintained, but revisited and modified in view of the claim amendments.
Declarations
The declarations under 37 CFR 1.132 filed on November 24, 2025 are insufficient to overcome the rejections under 35 U.S.C. 112(a), first paragraph, sets forth in the Office action and are addressed in the response to arguments sets forth below.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1, 5, 9, 13-14, 17-18, 51-52, 54-56 remain 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.
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 and discussed below:
(1, 5) The breadth of the claims and the Nature of the Invention: 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.”
Instant claims 1 recites “[a] method of treating cystitis in a subject, comprising: selecting a subject with cystitis; and administering to the subject a therapeutically effective amount of a purine nucleoside phosphorylase (PNPase) inhibitor, wherein the PNPase inhibitor is a guanine comprising a substituent at the 8-position… thereby treating the cystitis in the subject”. The breadth of the claims covers each and every cystitis species, and any therapeutically effective amount of each and every compound species of purine nucleoside phosphorylase inhibitor encompassed by the claimed list.
Instant claim 56 recites “[a] method of treating cyclophosphamide (CYP)-induced cystitis in a subject, comprising: selecting a subject with CYP-induced cystitis; and administering to the subject a therapeutically effective amount of 8-aminoguanine, thereby treating the CYP-induced cystitis”. The breadth of the claims covers any therapeutically effective amount of 8-aminoguanine for any subject species with CYP-induced cystitis.
(2, 3, 4) The state of the prior art, the level of skill in the art, and the predictability or lack thereof in the art: As stated in MPEP 2164.05(a), “[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 claimed invention is drawn to a method of treating the full scope of cystitis comprising administering to any subject species any therapeutically effective amount of each and every species of PNPase inhibitor instantly claimed.
According to Jackson et al. (WO 2018/045045 A1; cited in the IDS filed on August 30, 2021), purine nucleoside phosphorylase inhibitor, including 8-substitued guanosine and 8-substitued guanine such as 8-aminoguanine, exerts diuretic/natriuretic activity and promote natriuresis in a subject, including a veterinary subject or a human subject (see e.g., abstract; p. 32, line 2-3; p. 33, line 30 to P. 34, line 6). Jackson et al. further teaches natriuretic causes an increase in the excretion of sodium through urine (see e.g., p. 17, line 19). Based on the cited reference, one skilled in the art would have known that the use of purine nucleoside phosphorylase inhibitor will increase urine flow to the bladder, which in turn results in distention of the bladder. According to Burnstock (Purinergic Signal., 2014. Vol. 10(1): 103-55; cited in the Non-Final Office Action mailed on September 28, 2024), distention of the bladder leads to local release of ATP from epithelium lining of the bladder, which then activate P2X2/3 receptors on subepithelial sensory nerves to convey nociceptive signals to the CNS, causing pain (see e.g., Figure 2a). According to Moss et al. (Am J Physiol, 1997. Vol. 272(2): R695-703; cited in the IDS filed on June 10, 2025), rapid filling of the bladder causes a bursting activation of bladder chemoreceptive afferent nerves in hypogastric nerves, which could signal noxious overdistension and/or inflammation of the bladder (see e.g., abstract). According to Fort Worth Center for Pelvic Medicine (“Interstitial Cystitis” [Online]), patients with interstitial cystitis have a deficiency in the layer of mucus that protects the bladder wall from the saltiness of the urine; and therefore, salt-bearing foods and higher salt loads to the kidneys will result in an increase of symptoms (see e.g., “What causes interstitial cystitis?” section). In other words, natriuretic effect of purine nucleoside phosphorylase inhibitor is known in the art to exacerbate the symptoms of cystitis, including activating P2X2/3 receptors that convey nociceptive signals to the CNS, activating bladder chemoreceptive afferent nerves in hypogastric nerves to cause inflammation, and irritates bladder wall. Each of these cited references demonstrate that the state of the art with respect to administering any purine nucleoside phosphorylase inhibitor for treating cystitis is still underdeveloped, because one would expect that said inhibitors will exacerbate cystitis by promoting sodium excretion in the urine.
At the time the invention was made, the relative skill of those in the art tasked with treating cystitis with any therapeutic effective amount of any purine nucleoside phosphorylase inhibitor would have been low, as the ordinarily skilled artisan would have expected that the natriuretic effect of purine nucleoside phosphorylase inhibitor will exacerbate the pain and inflammation of cystitis by targeting the pathway discussed above.
Therefore, it is uncertain whether administering any therapeutic effective amount of any purine nucleoside phosphorylase inhibitor to any subject species can successfully treat the full scope of cystitis because it is highly unpredictable that said inhibitor will not exacerbate pain and inflammation of cystitis for the reasons set forth herein.
(6, 7, 8) The amount of guidance given, the presence of working example and the quantitation
of experimentation required:
In view of all of the foregoing, at the time the application was filed, it would have required undue experimentation to practice the full scope of the claimed invention. In the present case, example 7 of instant specification discloses the rats in group 3 were treated with 5mg/kg/day of oral 8-aminoguanine (8-AG) starting one week prior to cyclophosphamide (CYP) (see e.g., p. 60, line 16-21). The specification further discloses the rats received an i.p. injection of cyclophosphamide at a dose of 75 mg/kg on day 0, 3, 6, sacrifice day 8 to induce bladder inflammation, which is a well-established pre-clinical model for bladder pain syndrome/interstitial cystitis (BPS/IC) (see e.g., p. 60, line 16-21). The specification further discloses the results of Example 7 in Example 8, and that discloses 8-AG treatment abolish the CYP-induced bladder hyperemia, reduce the levels of pro-inflammatory cytokines (IL-1beta and MCP-1 mRNA) near the detection limit, return the mechanical pain threshold, and abolish significant inflammation and bleeding of the bladder (see e.g., p. 61, line 41 to P. 62, line 15). In other words, the specification does not provide an example of selecting a subject with cystitis, and administering to the subject a therapeutically effective amount of a PNPase inhibitor for treating cystitis. In fact, the specification only provides examples for preventing cystitis, because the PNPase inhibitor, in this case, 8-aminoguanine, was administered before the rats develop bladder pain syndrome/interstitial cystitis from the injection of cyclophosphamide. The disclosure does not have any data with respect to administering any therapeutically effective amount of any PNPase inhibitor species to any subject that already has bladder pain syndrome/interstitial cystitis. Therefore, one of the relative skill in the art could not reasonably predict which species of PNPase inhibitor encompassed by the claims could successfully treat the full scope of cystitis, including CYP-induced cystitis, without exacerbating cystitis based on the limited disclosure. Therefore, it would require an undue experimentation as it is highly unpredictable that administering any therapeutically effective amount of any species of PNPase inhibitor, including 8- aminoguanine, to any subject species would, in fact, be treating the full scope of cystitis, including CYP-induced cystitis.
Accordingly, the method of treating the full scope of cystitis in any subject with cystitis comprising administering to said subject any therapeutically effective amount of each and every species of PNPase inhibitor is not enabled by the instant specification.
Response to Arguments
Applicant's arguments filed on November 24, 2025 with respect to the rejection of claims 1-5, 9, 13-14, 17-18, 51-52, and 54-56 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 have been fully considered but they are not persuasive for the reasons sets forth below.
In the present case, Applicant amends claim 1 by incorporating the limitations previously recites in claims 2-4, and cancelled claims 2-4; therefore, the previous rejection on the record has been revisited and modified in view of the claim amendments.
In Summary, applicant argues the cyclophosphamide (CYP) treated rats in Example 8 of the present specification is an art-accepted animal model of cyclophosphamide induced cystitis; and the co-administration of the 8-AG and the CYP supports the full scope of the claims. Applicant further argues the declaration under 37 CFR 1.132 filed on November 24, 2025 provides evidence that demonstrate the PNPase inhibitor 8-AG is effective before or after treatment with CYP in the model of CYP-induced cystitis; therefore, an undue experimentation would not be required. Applicant further argue the amended claims now limits the use to only four specific compounds for cystitis (induced by any cause). Applicant further argues the enablement rejection is not an obviousness-type rejection; thus, one could practice the full scope of the invention based on the guidance in the specification itself; and only a limited amount of experimentation is required to practice the presently claimed methods.
In response, applicant’s argument is not found persuasive. First, the examiner acknowledged that the rejection on the record is an enablement rejection rather than an obviousness-type rejection. It is noted that the references recite therein is to demonstrate 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. Specifically, the purine nucleoside phosphorylase inhibitors, including the claimed 8-substitued guanine (e.g., 8-aminoguanine), are known in the art to exert diuretic/natriuretic activity and promote natriuresis in the subject according to Jackson et al. (WO 2018/045045 A1) (see rejection above). One skilled in the art would have also known that the natriuresis effect of said purine nucleoside phosphorylase inhibitors can increase the symptoms of interstitial cystitis, because patients with interstitial cystitis have a deficiency in the layer of mucus that protects the bladder wall from the saltiness of the urine; and it is known that higher salt loads to the kidneys will result in an increase of symptoms of said cystitis according to Fort Worth Center for Pelvic Medicine (“Interstitial Cystitis” [Online]). One skilled in the art would have also known that when the urinary bladder fills and stretches (distends), the epithelium lining of the bladder releases increased amounts of ATP that triggers pain in bladder pain syndrome patients according to Burnstock (Purinergic Signal., 2014. Vol. 10(1): 103-55). In other words, these cited evidences are used to demonstrate the state of the art and the unpredictability surrounding the use of diuretic/natriuretic, in this case, purine nucleoside phosphorylase inhibitors, for treating the entire scope of cystitis, including interstitial cystitis. Additionally, the claimed term “treating” when reasonably construed in light of page 13, line 23-31 of instant specification, it used to refer to a therapeutic intervention that ameliorate a sign or symptoms of a disease or pathological condition after it has begun to develop, in which ameliorate refers to any observable beneficial effect of the treatment, for example, a reduction in severity of some or all clinical symptoms of the disease. In other words, the natriuretic effect of purine nucleoside phosphorylase inhibitor is known in the art to increase symptoms of interstitial cystitis at the time the application was filed; therefore, one skilled in the art would not have known which purine nucleoside phosphorylase inhibitor can be employed at any therapeutically effective amount for treating the entire scope of cystitis at the time the application was filed.
In response to Applicant’s argument that Example 8 of the present specification and the declaration under 37 CFR 1.132 filed on November 24, 2025 support the full scope of claims, said assertion is not commensurate in scope with the claimed invention. First, the methods used to obtain the results for Example 8, which applicant relies, is described in Example 7 shown below (see page 60 of the specification):
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. It is noted that the “CYP/8-AG-treated rats” in Example 7-8 is referring to group 3 that received oral 8-AG at 5 mg/kg/day starting one week prior to cyclophosphamide. In contrast, instant claims pertain to “selecting a subject with cystitis; and administering to the subject…” (see instant claims 1 and 56), such that the subject has to have cystitis when the claimed PNPase inhibitor is being administered. In other words, the subjects in group 3 that received the 8-AG is not a subject with cystitis before said administration, and that is not commensurate in scope with the claimed invention.
Furthermore, the additional evidence disclosed in the declaration under 37 CFR 1.132 filed on November 24, 2025 upon which applicant relies is described in numbered list 4-5. Specifically, the declarant stated further experiment were conducted by administering oral 8-AG 14 days prior to CYP administration (pretreatment group) or 24 hours after CYP administration (posttreatment group) to the rats, and the voiding behavior and tactile sensitivity in both pre- and post-treatment groups were similar to the control, untreated rats (no CYP treatment); However, the experiment described therein does not mentioned the therapeutically effective amount of 8-AG being administered to the rats in both pretreatment group and posttreatment group. Said declaration also does not mention the dosing schedule of cyclophosphamide used to create the model of cyclophosphamide-induced cystitis in rats.
In contrast, instant claim 1 recites “[a] method of treating cystitis in a subject, comprising: selecting a subject with cystitis; and administering to the subject a therapeutically effective amount of a purine nucleoside phosphorylase (PNPase) inhibitor, wherein the PNPase inhibitor is a guanine comprising a substituent at the 8-position, a guanosine comprising a substituent at the 8-position, an inosine comprising a substituent at the 8-position, a hypoxanthine comprising a substituent at the 8-
position, or a pharmaceutically acceptable salt thereof, and wherein the substituent is amine”. In other words, the breath of the claims pertains to a method of treating the entire scope of cystitis in any subject, comprising selecting any subject with cystitis; and administering any therapeutically effective amount of each and every species of purine nucleoside phosphorylase (PNPase) inhibitor instantly claimed. Instant claim 56 recites “[a] method of treating cyclophosphamide (CYP)-induced
cystitis in a subject, comprising: selecting a subject with CYP-induced cystitis; and administering to the subject a therapeutically effective amount of 8-aminoguanine, thereby treating the CYP-induced cystitis”. The breadth of claim 56 pertain to a method of treating cyclophosphamide (CYP)-induced
cystitis in any subject, comprising selecting any subject with cystitis; and administering any therapeutically effective amount of 8-aminoguanine.
It is noted that the declarant only exemplified a single method species by administering a species of PNPase inhibitor (oral 8-aminoguanine) through a single route (oral) to a single subject species (a rat with CYP-induced cystitis), and that does not provide adequate basis for concluding that similar results would be obtained when administering other PNPase inhibitor through other routes to any other subject species (e.g., human) with other species of cystitis (e.g., cystitis caused by bacterial infection). In addition, the declarant does not describe the therapeutically effective amount of 8-aminoguanine used in the post-treatment group, and that does not provide adequate basis for concluding that similar results would be obtained using any therapeutically effective amount of each and every species of the claimed PNPase inhibitor, including 8-aminoguanine. The declarant also does not describe the dosing schedule of CYP used to establish the model of CYP-induced cystitis in rat.
Solely to rebut applicant’s argument that the animal model of cyclophosphamide induce cystitis is an art-accepted model that supports treating the entire scope of cystitis (induced by any cause) in any species at the time the application was filed, according to Creative Biolab (“Cyclophosphamide (CYP) induced Cystitis Modeling & Pharmacodynamics Service” [Online]), the model of cyclophosphamide-induced cystitis primarily focuses on the inflammatory response and may not fully replicate the underlying cause of all cystitis forms, such as infection-induced cystitis (see e.g., “Cyclophosphamide (CYP)-Induced Cystitis Model” section). In other words, the animal model of cyclophosphamide-induced cystitis is not known in the art to replicate all forms of cystitis, including infection-induced cystitis. Additionally, according to Augé et al. (Front Pharmacol, 2020. Vol. 11: 1305 ), there is lack of appropriate preclinical model for interstitial cystitis/bladder pain syndrome; while chemotherapeutic drug cyclophosphamide (CYP) is commonly used as an experimental model for IC/BPS in rodent, the proposed model are very aggressive, contrasting with what occurs in clinic, and often associated with severe toxicity and high mortality rate (see e.g., abstract). Furthermore, according to Abdel‐Samea et al. (Arch Pharm (Weinheim), 2025. Vol. 358(12): e70171.), despite promising results in the rat model of cyclophosphamide‐induced cystitis, using only rats may not accurately replicate human cyclophosphamide‐induced cystitis complexities, limiting direct extrapolation to clinical settings (see e.g., p. 9, right column, last paragraph). In other words, one skilled in the art would have known that the rat models treated with cyclophosphamide may not accurately replicate human cyclophosphamide‐induced cystitis as it is more aggressive than what it occurs in the clinical settings; Therefore, the quantity of experimentation necessary to carry out the entire scope of the claimed invention is high, because one of the relative skill in the art could not reasonably predict which of the claimed PNPase inhibitor species administered at any therapeutically effective amount through any administration route can successfully be adapted for treating each and every species of cystitis in any subject species based on the limited example provided by the Applicant.
Since the evidence/example upon which applicant relies is not commensurate in scope with the claim invention, it would have required undue experimentation to practice the full scope of the claimed intention based on the unpredictability surrounding the treatment of cystitis using a diuretic/natriuretic (purine nucleoside phosphorylase inhibitors) and the limited examples provided by the Applicant.
Therefore, the rejection is maintained, but revisited and modified in view of the claim amendments.
Claims 1, 9, 13-14, 17-18, 51-52 and 54-55 remain 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Instant claim 1 recites “[a] method of treating cystitis in a subject, comprising: selecting a subject with cystitis; and administering to the subject a therapeutically effective amount of a purine nucleoside phosphorylase (PNPase) inhibitor, wherein the PNPase inhibitor is a guanine comprising a substituent at the 8-position… thereby treating the cystitis in the subject”.
While applicant is in possession of 8-aminoguanine for treating cystitis, applicant is not in possession of the claimed genus of PNPase inhibitor for treating cystitis.
The written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, reduction to drawings, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical and/or chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show the inventor was in possession of the claimed genus. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. See Juno Therapeutics, Inc. v. Kite Pharma, Inc., 10 F.4th 1330, 1337, 2021 USPQ2d 893 (Fed. Cir. 2021).
In the presents case, applicant only provide examples of a method of treating cystitis species by specifically administering 8-aminoguanine as the only PNPase inhibitor as the only representative species. No other PNPase inhibitors were described in the specification for treating cystitis. As such, there does not appear to be a sufficient amount of representative method species that are described in the specification. A person of ordinary skill in the art would not be able to extrapolate the administration of 8-aminoguanine as the PNPase inhibitor to other structurally related PNPase inhibitor that can treat cystitis. According to Jackson et al. (WO 2018/045045 A1), PNPase inhibitor exerts diuretic/natriuretic activity and promote natriuresis in a subject, which increases the excretion of sodium through urine (see e.g., abstract; p. 32, line 2-3; p. 33, line 30 to P. 34, line 6; p. 17, line 19). Burnstock (Purinergic Signal., 2014. Vol. 10(1): 103-55) teaches distention of the bladder leads to local release of ATP from epithelium lining of the bladder causing pain (see e.g., Figure 2a). Moss et al. (Am J Physiol, 1997. Vol. 272(2): R695-703; cited in the IDS filed on June 10, 2025) teaches rapid filling of the bladder could signal noxious overdistension and/or inflammation of the bladder (see e.g., abstract). Fort Worth Center for Pelvic Medicine (“Interstitial Cystitis” [Online]) teaches higher salt loads to the kidneys will result in an increase of symptoms of interstitial cystitis (see e.g., “What causes interstitial cystitis?” section). In other words, each of these cited references demonstrate the level of skill and knowledge in the art with respect to administering the full scope of PNPase inhibitor in any therapeutic effective amount for treating cystitis is still underdeveloped, because natriuretic effect of PNPase inhibitor is known to exacerbate cystitis.
Since the specification fails to disclose any working examples using other species of PNPase inhibitor besides 8-aminoguanine, it is not apparent that Applicant was actually in possession of the entire genus of PNPase inhibitor for treating cystitis.
Accordingly, there is an insufficient written description for the claimed genus, aside from a broad recitation that the entire genus of PNPase inhibitor is contemplated for use in the invention. As such, it is not apparent that Applicant was actually in possession of, and intended to be used within the context of the present invention, to administer any PNPase inhibitor other than 8-aminoguanine for treating cystitis.
Accordingly, claims 9, 13-14, 17-18, 51-52, and 54-55 are also rejected based on their dependency on a rejected base claim.
Response to Arguments
Applicant's arguments filed on November 24, 2025 with respect to the rejection of claims 1-4, 9, 13-14, 17-18, 51-52 and 54-55 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 have been fully considered but they are not persuasive for the reasons sets forth below.
In the present case, Applicant amends claim 1 by incorporating the limitations previously recites in claims 2-4, and cancelled claims 2-4. Specifically, claim 1 now recites the limitation of”
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”; therefore, the previous rejection on the record has been revisited and modified in view of the claim amendments.
In Summary, Applicant argues the claim amendment now limits claim 1 to specific compounds (see the limitation cited above) that can be found in instant specification. Applicant further argues presenting a working example for each inhibitor species of the claimed genus is not required to satisfy the written description requirement. Applicant further argues 8-aminoguanosine is a prodrug that is converted in vivo to 8-aminoguanine; therefore, 8-aminoguanosine will exert the same effect as 8-aminoguanine in vivo. Applicant further argues inosine differs from guanosine only in the lack of an amino group in the 2-position of the purine ring, and likewise, hypoxanthine differs from guanine in the same manner; therefore, the structural parallel between the 8-aminoguanosine/8-aminoguanine pair and the 8-aminoinosine/8-aminohypoxanthine pair is striking, and one skilled in the art would reasonably understand that 8-aminoguanosine, 8-aminoinosine, and 8-aminohypoxanthine will exert the same effect demonstrated in the present application for 8-aminoguanine.
In response, applicant’s argument is not found persuasive. First, the rejection on the record is form on the basis that there is lack of representative number of method species as to reasonably convey to one skilled in the relevant art that the applicant is in possession of the generic method instantly claimed. The specification only taught one particular method of administering oral 8-AG (5 mg/kg/day) to a rat one week prior to cyclophosphamide in Example 7-8 shown below (see page 60 of the specification):
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. Based on the limited disclosure provided, it is not apparent that the Applicant was actually in possession of the entire scope of treating the entire scope of cystitis in any subject comprising selecting any subject with each and every species of cystitis; and administering to the subject any therapeutically effective amount of each and every species of purine nucleoside phosphorylase (PNPase) inhibitor instantly claimed.
Solely to rebut applicant’s argument that working examples for each inhibitor species of the claimed genus is not required to satisfy the written description requirement because the structural parallel between the claimed PNPase inhibitors will exert the same effect as the 8-aminoguanine, according to Bolton et al. (Journal of cheminformatics, 2011. Vol. 3, 13), the "Similar Compounds" relationship is useful to relate analogues that may have similar biological activity or function and additional biological annotation; however, "Similar Compounds" is not particularly good at finding chemical structures that can adopt similar 3-D shape and similar 3-D orientation of functional groups typically used to define pharmacophore features (henceforth, these pharmacophore feature functional groups will be referred to as "pharmacophore features" or simply as "features"), which could indicate, for example, that the molecules bind to a protein in a similar fashion (see e.g., p. 2, left column, 2nd paragraph). In other words, structurally similarity (or “structural parallel”) between two molecules does not guarantee the same pharmacological effect in medicinal chemistry, because the difference in pharmacophore can impacts a drug’s function. For instance, the claim recites “a hypoxanthine comprising a substituent at the 8-position...and wherein the substituent is amine” and “a guanosine comprising a substituent at the 8-position… and wherein the substituent is amine” in the list of PNPase inhibitor. Please note hypoxanthine has the structure of
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(see e.g., p. 23 of instant specification); and guanosine has the structure of:
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(see e.g., p. 22 of instant specification); However, according to Piazza et al. (US 6,200,980 B1), 2-(2-propoxyphenyl)-8-aminopurin-6-one is a compound for inhibiting precancerous lesions (see e.g., Col. 3, line 15-21; Col. 16, “Example 41”). Although said compound contains a purine just like 8guanosine and hypoxanthine, it is not recognized to have PNPase inhibiting effect. Furthermore, according to Gandhi et al. ([haematologica reports], 2006. Vol. 2(13): 35-37), an oral formulation of PNPase inhibitor forodesine showed 63% bioavailability in mice but much lower primates. In other words, PNPase inhibitor forodesine, which also contains a purine, is known to exhibit significant difference in bioavailability across different subject species; and therefore, it is not apparent that each and every PNPase inhibitor instantly claimed is capable of exerting the same effect in any subject species through any route of administration at any therapeutically effective dose.
Therefore, the rejection is maintained, but revisited and modified in view of the claim amendments.
Conclusion
No claims are allowed.
THIS ACTION IS MADE FINAL. Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
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/CHIHYI LEE/Examiner, Art Unit 1628 /JEAN P CORNET/Primary Examiner, Art Unit 1628