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 .
Current Status
This action is responsive to the amended claims of 06/16/2026. Claims 18, 20, 24, 32, 34, 36, 39, 45, 51, and 55-65 are pending. Claims 51 and 55 are withdrawn.
Claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65 have been examined on the merits.
Election/Restrictions
Applicant's election with traverse of Group II (claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65) in the reply filed on 06/16/2026 is acknowledged. The traversal is on the ground(s) that the restriction requirement relied on RN 3240-35-5 (previously provided) as the basis for lack of unity of invention. The claims have been amended so they no longer encompass the RN, they are drawn solely to probenecid. This is not found persuasive because, while the shared technical feature of the Groups I and II is now probenecid, probenecid does not make a contribution over the prior art in view of WOLF (Wolf, D.L. et al., J. Clin. Pharmacol., 2003, 43, 43-51). WOLF discloses probenecid and its use to reduce nephrotoxicity associated with antiviral treatment with cidofovir (Pg. 43 abstract). Thus, the shared technical feature probenecid cannot be a special technical feature. Therefore, the Groups I and II still lack unity of invention.
The requirement is still deemed proper and is therefore made FINAL.
Applicant’s election without traverse of the species: probenecid, viral infection Ebola, fever, and human in the reply filed on 06/16/2026 is acknowledged.
A search for the elected species: combination of probenecid and ebola did not retrieve any prior art. Thus, the search was expanded to the viruses recited in claims 24 and 65 – no art was found. The search was further expanded and retrieved art for the species of viral infection: HIV (RNA virus of family Retroviridae), Cytomegalovirus (DNA virus of family Herpesviridae), and Adenoviridae (family of DNA viruses). Per Markush search practice, the Markush search will not be extended unnecessarily to additional species in this Office Action.
The searched species read on claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65.
Claims 51 and 55 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention, there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on 06/16/2026.
To expedite prosecution: please cancel unelected Group I claims 51 and 55. Since these are product/composition of matter claims, these claims will not be eligible for rejoinder (see MPEP 821.04).
Priority
The effective filing date is 07/06/2021.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on 01/25/2024, 02/15/2024, 03/07/2024, 07/18/2025, and 06/10/2026 are in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claims 32, 61, and 65 are objected to because of the following informalities. Appropriate correction is required.
Claim 32: please strike the word “are” from the phrase “the subject has one or more symptoms are selected from”.
Claim 61: please add the word “administered” to line 2 as follows: “salt thereof is administered at a dosage of”.
Claim 65: please add the word “of” to line 3 as follows: “amount of probenecid”.
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 18, 20, 24, 32, 34, 36, 39, 45, and 56-65 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for treatment or prevention of viral infections due to measles, mumps, dengue, and zika, does not reasonably provide enablement for treatment or prevention of any viral infection due to a non-respiratory virus. The art also provides enablement for treatment and prevention of HIV, adenovirus, and cytomegalovirus (CMV). The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to practice the invention commensurate in scope with these claims. This is a scope of enablement rejection.
The Wands Factors used in a scope of enablement rejection include (per MPEP 2164.01(a)):
The breadth of the claims:
The claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65 are drawn to a method of treating or preventing non-respiratory viral infection by administration of probenecid to a subject. The claims are very narrow in the compound administered (probenecid). However, the claims are very broad regarding the viral infection treated/prevented; any viral infection is encompassed as long as the virus is not a respiratory virus. Claims 24, 59, and 65 recite a handful of species of virus: Zika, dengue, yellow fever, Japanese encephalitis, West Nile, and Hepatitis A-C; ebola; and hantavirus. Claims 56-58 are drawn to specific families of virus, somewhat narrowing the scope of treatment/prevention.
The nature of the invention:
The invention belongs to pharmaceutical technology: use of probenecid to treat or prevent viral infections caused by non-respiratory viruses.
The state of the prior art & predictability of the art:
The prior art only teaches treatment/prevention of a handful of viruses by administration of probenecid. WOLF (Wolf, D.L. et al., J. Clin. Pharmacol., 2003, 43, 43-51) discloses administration of probenecid and antiviral cidofovir for treatment of cytomegalovirus (Pg. 43 Abstract). CIMSIT (Cimsit, B. et al., Pediatr. Transplantation, 2012, 16, E90-E93) discloses administration of cidofovir is standard for treatment of adenovirus (Pg. E90 Left col. ¶2) wherein oral probenecid is also given to protect kidney function (Pg. E91 Right col. ¶1-2). LIU (Liu, S.N. et al., Clinical Pharmacology & Therapeutics, May 2020, 107(5),1200-1208) discloses administration of probenecid with HIV prophylactic drugs TDF and FTC increased plasma exposure and decreases renal clearance thereof (Pg. 1205 Discussion). LUCIA (Lucia, M.B. et al., J. acquir. Immune Defic. Syndr., 2005, 40(3), 257-266) discloses probenecid downregulates HIV-1 replication (Pg. 257 Summary). Thus, the art provides guidance from which the artisan would be able to achieve, with reasonable experimentation, treatment of cytomegalovirus (CMV), adenovirus, and HIV and prevention of HIV.
In view of the relevant prior art, the artisan would be enabled to use probenecid to treat viral infections from adenovirus, HIV, and cytomegalovirus and prevent HIV. However, there is a lack of art disclosing the use of probenecid to treat and/or prevent other viral infections, especially those beyond the scope of respiratory viruses, the art does not provide enablement for treatment or prevention of any and all viral infections caused by non-respiratory viruses.
The level of one of ordinary skill:
The relative skill of those in the art is high, generally that of an M.D. or Ph.D. The artisan using Applicant's invention would generally be a physician with an M.D. degree and several years of experience. This factor is outweighed, however, by the unpredictable nature of the art (established above). It is well established that "the scope of enablement varies with the degree of unpredictability of the factors involved" and physiological activity is 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).
The amount of direction provided by the inventor and the existence of working examples:
Inventors have provided data for probenecid therapy in various viral infection models (see Figures 1-26 of the instant Specification); however, a vast majority of the data provided is collected on treatment/prevention of respiratory-viruses. The only non-respiratory viruses tested are: mumps (Fig. 10; Ex. 2 Pg. 156), Zika (Fig. 11; Ex. 2 Pg. 156), Dengue (Fig. 12; Ex. 2 Pg. 156), and measles (Fig. 14; Ex. 3 Pg. 157). No other non-respiratory viruses were tested. While the data for these viruses does show reduction of virus titer and inhibition of viral replication to levels at/below the limit of detection (i.e., treatment and prevention), this data cannot be extrapolated to the vast pool of non-respiratory viruses covered by the instant claims.
Zika and dengue belong to the same family (Flaviviridae) as 3 other species recited in claim 24: yellow fever, Japanese encephalitis, and West Nile. However, the lack of prior art evidence and/or instant evidence of overlap in treatment mechanism by probenecid introduces a burdensome level of experimentation required to treat and prevent other species of the same family. This is especially true for species which belong to other families. Thus, the same can be said for the further species and families recited in claims 24, 56-59, and 65.
Thus, Applicants have guidance/enablement in their Specification for treating and preventing mumps, Zika, dengue, and measles. The Specification lacks guidance for treating and preventing: 1) any and all non-respiratory viruses; 2) the claimed species: yellow fever, Japanese encephalitis, West Nile, and Hepatitis A-C (claim 24); ebola (claim 59); and hantavirus (claim 65); and 3) the full scope of the families recited in claims 56-58.
The quantity of experimentation needed to make or use the invention:
Applicants’ invention comprising treating/preventing non-respiratory viruses by administering probenecid requires a high level/quantity of experimentation to use the invention for treatment/prevention of any and all non-respiratory viruses. While Applicants have provided guidance in their Specification for treating/preventing mumps, Zika, dengue, and measles, they have not provided enough evidence that probenecid can be used to treat/prevent the full scope of non-respiratory viruses per the BRI of the instant claims. At best, with the guidance of the prior art and the specification, the artisan would be enabled to treat and prevent mumps, Zika, dengue, measles, and HIV and to treat adenovirus and CMV.
Therefore, claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65 are rejected under 35 USC 112(a) for lacking scope of enablement for the full scope of non-respiratory virus.
To render moot this scope of enablement rejection: Examiner suggests narrowing the scope of the claims to enabled viruses. Please verify written description support for such species.
Claim Rejections - 35 USC § 102
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.
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claims 18, 20, 34, 36, 45, 56, 60-61, and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by WOLF (Wolf, D.L. et al., J. Clin. Pharmacol., 2003, 43, 43-51) evidenced by MERRIAM (Cytomegalovirus. (2016). In Merriam-Webster (Ed.), Merriam-Webster’s Medical Dictionary (1st ed.). Merriam-Webster. Infobase. https://access.infobase.com/article/927899-cytomegalovirus?aid=279753).
Regarding claims 18, 36, and 45, WOLF teaches, to reduce nephrotoxicity, oral administration of probenecid must be used with each infusion of the antiviral cidofovir – this combination treatment was administered to human patients with cytomegalovirus (CMV) (Pg. 43 Abstract; Pg. 43-44 bridge ¶). Since the instant claims are drafted as a method “comprising” administration of probenecid, the administration of other drugs is not excluded. Since the probenecid is used to support treatment of CMV by reducing nephrotoxicity of the cidofovir, the probenecid is beneficial to and plays a role in the treatment of CMV. For claim 45, the “wherein” clause is placed after the second embodiment “(ii)”, thus, the “wherein” clause may be interpreted as only applying to embodiment (ii) and not embodiment (i).
Regarding claims 20 and 56, MERRIAM discloses CMV is a DNA herpesvirus (Pg. 1 sect. 1); i.e., family Herpesviridae.
Regarding claim 34, WOLF teaches the probenecid is administered as a 500 mg tablet (Pg. 45 Treatment ¶1). A tablet is understood as a pharmaceutical composition comprising a pharmaceutically acceptable carrier/excipient.
Regarding claim 60, WOLF teaches a group of 24 patients were treated wherein each patient was infected with the virus (Pg. 43 Abstract).
Regarding claim 61 and 63, WOLF teaches two administration regimens: 1) one 2 g dose followed by two 1 g doses of probenecid given once and 2) one 2 g dose given once (Pg. 45 Treatment ¶1-2). This corresponds to: 1) a 2,000 mg dose once a day and two 1,000 mg doses twice a day wherein the dose is only given one day and 2) a 2,000 mg dose once a day wherein the dose is only given one day. The other limitations of these claims are optional.
Claims 18, 20, 32, 34, 36, 45, 61, and 63-64 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by CIMSIT (Cimsit, B. et al., Pediatr. Transplantation, 2012, 16, E90-E93) evidenced by WEBSTER (Adenovirus. (2016). In Merriam-Webster (Ed.), Merriam-Webster’s Medical Dictionary (1st ed.). Merriam-Webster. Infobase. https://access.infobase.com/article/927903-adenovirus?aid=279753).
Regarding claims 18, 36, and 45, CIMSIT teaches adenovirus (AdV) hepatitis treatment comprising cidofovir and oral probenecid to protect kidney function (Pg. E91 Right col. ¶1-2) in a 16-month-old human patient (Pg. E90 Case Report). Since the instant claims are drafted as a method “comprising” administration of probenecid, the administration of other drugs is not excluded. Since the probenecid is used to support treatment of AdV by reducing nephrotoxicity of the cidofovir, the probenecid is beneficial to and plays a role in the treatment of AdV. For claim 45, the “wherein” clause is placed after the second embodiment “(ii)”, thus, the “wherein” clause may be interpreted as only applying to embodiment (ii) and not embodiment (i).
Regarding claim 20, WEBSTER discloses AdV is a DNA virus of the family Adenoviridae (Pg. 1).
Regarding claim 32, CIMSIT teaches the patient is symptomatic with a fever (Pg. E91 Left col. ¶2)
Regarding claim 34 and 36, CIMSIT teaches the probenecid is administered orally (Pg. 45 Treatment ¶1). Since the probenecid is being given to a human patient orally, the artisan would immediately envisage the oral dose as a pharmaceutical composition comprising a pharmaceutically acceptable carrier/excipient (e.g., a tablet or solution).
Regarding claim 61 and 63-64, CIMSIT teaches a 1.25 g/m2 probenecid dose once a day (Pg. E91 Right col. ¶1-2); treatment was continued for 22 days (Pg. E91 Right col. ¶3-4). Converting from a body surface area-based dose this corresponds to about 600 mg/once a day. The other limitations of claims 61 and 63 are optional.
Claims 18, 20, 34, 36, 45, 60-61, and 63 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by LIU (Liu, S.N. et al., Clinical Pharmacology & Therapeutics, May 2020, 107(5),1200-1208) evidenced by MERRIAM-WEBSTER (Retroviridae. (2016). In Merriam-Webster (Ed.), Merriam-Webster’s Medical Dictionary (1st ed.). Merriam-Webster. Infobase. https://access.infobase.com/article/1007544-retroviridae?aid=279753).
Regarding claims 18, 36, and 45, LIU teaches probenecid as a booster for the HIV preexposure prophylaxis drugs: TDF/FTC (Pg. 1201 Left Col. ¶3). A combination pill of TDF/FTC is used to prevent HIV infection (Pg. 1200 Study Highlights). Healthy, human volunteers were administered 2 g probenecid and 600/400 mg of TDF/FTC with ~250 mL water (Pg. 1201 Methods ¶1-4). The administration was oral (Pg. 1205 Discussion). The probenecid increased plasma exposure and decreased total and renal clearance of the TDF/FTC drug combination (Pg. 1205 Discussion); further, after 24 hours the intracellular concentration of the TDF/FTC drug was significantly increased compared to a control without probenecid (Pg. 1206 Left col. ¶1). Since the instant claims are drafted as a method “comprising” administration of probenecid, the administration of other drugs is not excluded. Since the probenecid is used to boost the HIV prophylactic drugs, the probenecid is beneficial to and plays a role in the prophylaxis/prevention of HIV. For claim 45, the “wherein” clause is placed after the second embodiment “(ii)”, thus, the “wherein” clause may be interpreted as only applying to embodiment (ii) and not embodiment (i).
Regarding claim 20, MERRIAM-WEBSTER discloses HIV is an RNA virus of family Retroviridae (Pg. 1).
Regarding claim 34 and 36, LIU teaches the probenecid is administered orally with water (Pg. 1201 Methods ¶1-4). The artisan would immediately envisage the oral dose as a pharmaceutical composition comprising a pharmaceutically acceptable carrier/excipient (e.g., a tablet).
Regarding claim 60, LIU teaches a group of 14 healthy volunteers were treated with the probenecid + TDF/FTC prophylaxis (Pg. 1200 Abstract). Thus, a group of subjects not infected with the virus are treated.
Regarding claim 61 and 63, LIU teaches a 2 g probenecid dose once (Pg. 1201 Methods ¶1-4); i.e., 2,000 mg once a day wherein the dose is only given one day. The other limitations of these claims are optional.
Claim Rejections - 35 USC § 103
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.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 18, 20, 32, 34, 36, 39, 45, and 60 are rejected under 35 U.S.C. 103 as being unpatentable over:
LIU (Liu, S.N. et al., Clinical Pharmacology & Therapeutics, May 2020, 107(5),1200-1208) evidenced by MERRIAM-WEBSTER (Retroviridae. (2016). In Merriam-Webster (Ed.), Merriam-Webster’s Medical Dictionary (1st ed.). Merriam-Webster. Infobase. https://access.infobase.com/article/1007544-retroviridae?aid=279753), as applied to claim 18 above,
further in view of LUCIA (Lucia, M.B. et al., J. acquir. Immune Defic. Syndr., 2005, 40(3), 257-266) evidenced by STANFORD (Stanford Health Care, “Symptoms of HIV and AIDS,” captured 2018, retrieved from https://web.archive.org/web/20180313155940/https://stanfordhealthcare.org/medical-conditions/sexual-and-reproductive-health/hiv-aids/symptoms.html),
and further in view of WOLF (Wolf, D.L. et al., J. Clin. Pharmacol., 2003, 43, 43-51).
The instant claims are drawn to a method of treating or preventing infection by a non-respiratory RNA virus by administering probenecid to a subject(s) (18, 20, & 60) wherein the subject is symptomatic/asymptomatic (32). The probenecid is orally administered (34) to a human in a food-based pharmaceutical composition (36 & 45) and reduces viral replication (39).
Determining the Scope and Contents of the Prior Art:
LIU teaches the method of claim 18 wherein HIV infection is prevented (see 102 rejection ¶20). LIU teaches HIV is transmissible (Pg. 1200 Left col. ¶1). Further, LIU, evidenced by MERRIAM-WEBSTER, teaches the limitations of claims 20, 34, 36, 45, and 60 (¶20).
LUCIA teaches MRP function favors HIV-1 infection; HIV-1 infected cells were incubated with MRP-specific inhibitor probenecid; after 5 days probenecid decreased HIV-1 p24 antigen levels by ~30%; probenecid has inhibitory effects on HIV-1 replication (Pg. 262 Left col. ¶2 – Right col. ¶1). In cells from individuals with symptomatic primary HIV infection, probenecid significantly reduced in vitro HIV-1 replication (Pg. 264 Right col. ¶1). STANFORD discloses symptoms of HIV infection include fever, headache, malaise, and lack of energy (Pg. 1).
WOLF teaches gastrointestinal upset is reduced when probenecid is taken with food (Pg. 45 Left col. ¶4).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
LIU does not teach treatment of HIV infection, symptomatic patients, probenecid reduces viral replication, or probenecid formulated in the subject’s food.
LUCIA does not teach in vivo administration to a subject.
WOLF does not teach prevention/treatment of HIV.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods useful for treatment of HIV and possesses the technical knowledge necessary to make adjustments to the method enhance the outcomes. Said artisan has also reviewed the problems in the art regarding HIV replication and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references LIU (evidenced by MERRIAM-WEBSTER), in view of LUCIA (evidenced by STANFORD), and in view of WOLF.
Regarding claim 18, 20, and 39, the artisan would be motivated to utilize probenecid in both treatment and prevention of HIV infection since probenecid inhibits HIV-1 replication, as recognized by LUCIA (Pg. 264 Right col. ¶1). Since LIU teaches effective use of probenecid in human subjects (see above ¶20), the artisan would have an expectation of success in transferring LUCIA’s findings to practice in human subjects and would be motivated to administer probenecid in an amount that reduces viral replication.
Regarding claim 32, the artisan would have an expectation of success in treating symptomatic HIV infection since LUCIA reports significantly reduced HIV-1 replication in cells from symptomatic patients (Pg. 264 Right col. ¶1). These symptoms may include fever, headache, fatigue/tiredness, as recognized by STANFORD (Pg. 1).
Regarding claim 34, 36, and 45, the artisan would be motivated to orally administer probenecid as a pharmaceutical composition formulated in the patient’s food in order to reduce gastrointestinal upset, as recognized by WOLF (Pg. 45 Left col. ¶4). The artisan would expect success since LIU teaches oral administration (Pg. 1201 Methods ¶1-4).
Regarding claim 60, the artisan would be motivated to treat a group of subjects, wherein all subjects are infected or only some subjects are infected, since HIV is transmissible (LIU Pg. 1200 Left col. ¶1). Further, since LIU & LUCIA together teach treatment and prevention of HIV (above), the artisan would have an expectation of success in treating/preventing infection in a group of mixed-infection-status subjects.
Claims 18 and 61-64 are rejected under 35 U.S.C. 103 as being unpatentable over:
LIU (Liu, S.N. et al., Clinical Pharmacology & Therapeutics, May 2020, 107(5),1200-1208),
in view of LUCIA (Lucia, M.B. et al., J. acquir. Immune Defic. Syndr., 2005, 40(3), 257-266)
as applied to claim 18 above, and
further in view of ANSEL (Ansel, H.C. et al. Pharmaceutical Dosage Forms and Drug Delivery Systems, Lippincott Williams & Wilkins, 7th ed., 1999, pages 48-53)
and further in view of IBRAHIM (Ibrahim, K.H. et al., Antimicrobial Agents and Chemotherapy, 2004, 4195-4199; cited IDS 01/25/2024).
The instant claims are drawn to a method of treating or preventing infection by a non-respiratory RNA virus by administering probenecid to a subject at a dose of: 10-2,000 mg once-twice daily for 14 days/2 weeks or more (61 and 63-64). The subject is treated by pulse dosing (62).
Determining the Scope and Contents of the Prior Art:
LIU & LUCIA teach the method of claim 18 wherein HIV infection is treated & prevented (see 103 rejection ¶25).
LIU teaches a 2 g probenecid dose once (Pg. 1201 Methods ¶1-4). The promise of effective prophylaxis depends on adherence to dosing regimens – daily dosing regimens can be burdensome; thus, reduced dose regimens can be more advantageous for adherence (Pg. 1201 Left col. ¶1-2).
LUCIA teaches 200 uM probenecid incubation for 5 days (Pg. 262 Left col. ¶2 – Right col. ¶1) and dose dependent effects of 250-1000 uM of probenecid on cell redox state (Pg. 264 Fig. 5).
ANSEL teaches the safe and effective dose of a drug depends on factors including drug characteristics, the dosage form, and a variety of patient factors (Pg. 48 Left Col. para 2); the effective dose may be different for different patients (Pg. 48 Left Col. para 4). The dosage schedule/regimen is determined based on a drug’s duration of action, pharmacokinetics, and dosage form (Pg. 40 Right Col. para 2).
IBRAHIM teaches pulse dosing produces escalating drug levels early in a dosing interval followed by a prolonged dose-free period (Pg. 4195 Abstract) – the advantage of such dosing is reduced dose frequency and greater patient compliance (Pg. 4195 Left-Right col. bridge ¶).
Ascertaining the Differences Between the Prior Art and the Claims at Issue:
LIU and LUCIA do not teach the full range of probenecid doses and schedules.
ANSEL and IBRAHIM, each, do not teach treatment/prevention of HIV.
Resolving the Level of Ordinary Skill in the Pertinent Art:
The level of ordinary skill in the art is represented by an artisan who has sufficient background in the development of methods useful for treatment of HIV and possesses the technical knowledge necessary to make adjustments to the dosing regimen to optimize the treatment outcomes. Said artisan has also reviewed the problems in the art regarding HIV infection and understands the solutions that are widely-known in the art.
Considering Objective Evidence Present in the Application Indicating Obviousness or Nonobviousness:
The instant claims are prima facie obvious in light of the combination of references LIU, in view of LUCIA, in view of ANSEL, and in view of IBRAHIM.
Regarding claim 18, the combination of LIU and LUCIA teach the method of treatment and prevention, above ¶25.
Regarding claims 61-64, the artisan would be motivated to optimize the dosage amounts and schedule based on the teachings provided in the art.
MPEP 2144.05(II)(A) provides guidance about the routine optimization of prior art conditions: "Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). "The normal desire of scientists or artisans to improve upon what is already generally known provides the motivation to determine where in a disclosed set of percentage ranges is the optimum combination of percentages.").”
Furthermore, MPEP 2144.05(I) provides guidance about overlapping ranges: “In the case where the claimed ranges "overlap or lie inside ranges disclosed by the prior art" a prima facie case of obviousness exists…Similarly, a prima facie case of obviousness exists where the claimed ranges or amounts do not overlap with the prior art but are merely close.”
In the instant case, the LIU dosage of 2 g (2,000 mg once a day for 1 day) overlaps with the instantly claimed dosage/schedule (claims 61 and 63). Since ANSEL teaches the dosage regimen is based on duration of action, pharmacokinetics, and the dosage form (Pg. 40 Right Col. para 2) and the effective dosing may be different for different patients (Pg. 48 Left Col. para 4), the artisan would recognize the dosage amount and timings of probenecid as a result-effective variable, i.e., a variable that achieves a recognized result. Thus, the dosage is analogous to the “concentration or temperature” recited in the MPEP and may be optimized by routine experimentation. Further, based on the teachings of LUCIA (Pg. 262 Left col. ¶2 – Right col. ¶1; Pg. 264 Fig. 5), the artisan would expect dose dependent effects of probenecid and would be motivated to optimize the dose for treatment and prevention regimens. Since LUCIA teaches multiple days of probenecid exposure to inhibit HIV replication (Pg. 262 Left col. ¶2 – Right col. ¶1), the artisan would be motivated to also adjust the schedule of dosing. Absent any evidence demonstrating the contrary, the determination of the optimum or workable dosage amounts and schedule of probenecid would have been well within the practice of the artisan given the guidance of the prior art.
Further regarding claim 62, the artisan would be motivated to optimize dosing schedule for the reasons above. Further, the artisan would be motivated to utilize pulse dosing in order to improve medication adherence and efficacy of the treatment/prevention, as recognized by both LIU (Pg. 1201 Left col. ¶1-2) and IBRAHIM (Pg. 4195 Left-Right col. bridge ¶).
Conclusion
Claims 18, 20, 24, 32, 34, 36, 39, 45, and 56-65 are rejected.
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/S.E.B./Examiner, Art Unit 1625
/JOHN S KENYON/Primary Patent Examiner, Art Unit 1625
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