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 .
Priority
This Application filed on 01/27/2023, claims benefit of United States Provisional Application No. 63/058,870, filed on 07/30/2020, and PCT/US2021/043687 filed on 07/29/2021.
Information Disclosure Statement
The information disclosure statement (IDS) filed on 07/06/2023, and 07/26/2024, complies with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, it has been placed in the application file and the information therein has been considered as to the merits, except where noted.
DETAILED ACTION
Applicant amendment and argument filed on 11/05/2025 have been received and have been carefully considered.
Claim 1 is amended, claims 11-16, 26-30 and 32-40 are previously cancelled, and claim 41 is added.
Claims 1-10, 17-25, 31 and 41 are pending.
Claim interpretation
Examination requires claim terms first be construed in terms in the broadest reasonable manner during prosecution as is reasonably allowed in an effort to establish a clear record of what applicant intends to claim. See MPEP § 2111. Under a broadest reasonable interpretation, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification. See MPEP § 2111.01. It is also appropriate to look to how the claim term is used in the prior art, which includes prior art patents, published applications, trade publications, and dictionaries. MPEP § 2111.01 (III). However, specific embodiments of the specification cannot be imported into the claims, particularly where the subject claim limitation is broader than the embodiment. MPEP § 2111.01(II).
Claim interpretation for “likely to develop a disease”
Claim 1 recites “a method for treating a subject having or likely to develop a neurodegenerative disease …” Instant specification does not provide specific definition to the term “likely to develop a neurodegenerative disease”. The specification recites “In some embodiments, the neurodegenerative disease is characterized by one or more markers (such as a pathological marker) indicative of a neurodegenerative condition, the onset of a neurodegenerative condition, or a predisposition or likelihood of developing a neurodegenerative condition. [Pg. 11, [0035]].
As provided in MPEP 211.01 Ill, [T]he ordinary and customary meaning of a claim term is the meaning that the term would have to a person of ordinary skill in the art in question at the time of the invention, i.e., as of the effective filing date of the patent application. ("In the absence of an express intent to impart a novel meaning to the claim terms, the words are presumed to take on the ordinary and customary meanings attributed to them by those of ordinary skill in the art."). Where neither the claims, nor the specification, nor the prosecution history offer sufficient clarity on claim scope, extrinsic evidence may become a necessary part of claim interpretation. Moreover, MPEP 2111.01 stated that it is improper to “read limitations into a claim from the preferred embodiment described in the specification, even if it is the only embodiment described, absent clear disclaimer in the specification."
The term “likely to develop a neurodegenerative disease” is given its broadest reasonable interpretation and interpreted according to NCI Dictionary of Genetics Terms as: Increased likelihood or chance of developing a particular disease due to the presence of one or more gene mutations and/or a family history that indicates an increased risk of the disease. Also called genetic susceptibility. (Likely to develop a disease. (2018). NCI Dictionary of Genetics Terms. Retrieved from Internet Archive, website:
https://web.archive.org/web/20180724194552/https://www.cancer.gov/publications/dictionaries/genetics-dictionary/def/genetic-predisposition.
Claim interpretation for “hydrocarbon”:
Claim 1 recites “… wherein R is hydrocarbon… .” The instant specification defines the term “hydrocarbon” using different embodiments including composed solely of carbon and hydrogen; saturated or straight-chained or branched alkyl group; saturated and cyclic alkyl hydrocarbon group; unsaturated and straight-chained or branched hydrocarbon group; and unsaturated and cyclic hydrocarbon group. [0049]-[0055]. The term hydrocarbon is interpreted consistent with the instant specification.
Withdrawn Claim Objections
Objection to claim 1 for reciting -OPO32-, is withdrawn in view of Applicant amendment filed on 11/05/2025, that amended -OPO32- with -OPO3H2.
Withdrawn Claim Rejections - 35 USC § 102
Rejection to claims 1-4, 17-19, 23-25 and 31 under 35 U.S.C. 102(a)(1) as being anticipated by X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, is withdrawn in view of Applicant’s amendment filed on 11/05/2025, that amended claim 1 with “wherein the compound is administered by an extended-release formulation”.
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 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.
§ 103 Rejection over Pan in view of Paolini
Claims 1-4, 17-19, 23-25, and 31 are rejected under 35 U.S.C. 103 as being unpatentable over X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, “Pan” cited in the IDS dated 07/06/2023), in view of Paolini, Marion S. et al. "Polymers for extended-release administration." Biomedical Microdevices 21, 2 (April 2019): 45 © 2019 Springer Science Business Media, LLC, “Paolini” cited in the PTO-892).
Pan discloses a method of administering 50 mg/kg/day, 100mg/kg/day and 200mg/kg/day of benfotiamine for treating Alzheimer’s disease, wherein the administration of benfotiamine improves cognitive function and reduces amyloid deposition via thiamine-independent mechanisms, [Abstract, Page 1344, col. 2nd para.]:
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Pan’s subject is a rodent Alzheimer’s disease model: amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice (carrying both mutant APP and PS1 transgenes) [Pg. 1343, col. 2, 3rd para.].
Pan’s benfotiamine meets instant claimed formula (I), wherein:
the (rodent) subject is having or likely to develop Alzheimer’s disease, see claim interpretation above,
R1 is a hydrocarbon containing 7 carbon atoms and one oxygen atom (Instant specification recited benzyl as an example of hydrocarbon and recited that hydrocarbon can be substituted with O, [0055]-[0056]), see claim interpretation above;
R2 is -OPO3H2.
Pan meets the claim 1 limitations except for the recitation that the compound is administered in an extended-release formulation.
Paolini teaches extended-release drug delivery for extended periods of time, that provide with control release system (CRS) and minimal complication and distress for the patient. [Abstract].
Paolini teaches that patients with chronic conditions benefit from extended-release systems to avoid the burden that daily intake of pills or daily injections represent. Paolini teaches that these burdensome treatments which causes a lack of adherence in the treatment regimen for patients is due to multiple factors, including forgetting to take the treatment, and psychological barriers against taking a treatment. Paolini teaches “On top of facilitating the access and the adherence to treatments for patients’ population, CRS enable therapies targeted at difficult to reach areas of the body. Treatments in the joints, in the eye, or in the brain for instance can be either painful or technically difficult to realize. Implanting an CRS in these areas is a solution to prevent multiple interventions. CRS can therefore provide benefits to a vast number of patients, for many therapeutic indications.” [Pg. 4].
Therefore, one of ordinary skill in the art would have been motivated to formulate benfotiamine taught by Pan in an extended-release formulation for treating a subject having or likely to develop a neurodegenerative disease. One of ordinary skill in the art would have been motivated to do so with reasonable expectation of success because Paolini teaches the benefits of the extended-release system including minimal complication and distress for the patient, access to difficult areas of the body, etc. and teaches that extended-release system enable for avoiding the burdensome to the patients as listed on page 4. Moreover, one of ordinary skill in the art targeting the treatment of Alzheimer’s disease would have been motivated to specifically formulate Pan’s benfotiamine in an extended-release formula because Paolini teaches that this drug delivery system would particularly benefit patients who forgetting to take the treatment, and have psychological barriers against taking a treatment.
Therefore, the combination of Pan and Paolini meets each and every limitation of claims 1 and 4. Pan’s benfotiamine meets the limitations of claims 23, 24, 25 and 31.
Claims 2, 3 are met because Pan discloses that Alzheimer’s disease characterized by amyloid plaque in the brain and benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains, [Abstract].
Claims 17 and 18 are met because Pan’s subject is a rodent Alzheimer’s disease model: amyloid precursor protein (APP)/presenilin-1 (PS1) transgenic mice (carrying both mutant APP and PS1 transgenes) [Pg. 1343, col. 2, 3rd para.], therefore, the subject is testing for the presence of one or more markers, i.e., amyloid plaque in the brain.
Claim 19 is met because benfotiamine effectively reduced both amyloid plaque numbers and phosphorylated tau levels in cortical areas of the transgenic mice brains, [Abstract].
Claims 20-22 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, “Pan” cited in the IDS dated 07/06/2023) as applied above to claims 1-4, 17-19, 23-25 and 31, and as evidenced by The Jackson Laboratory (2020). Retrieved from the Internet Archive, website:
https://web.archive.org/web/20200812102334/https://www.jax.org/strain/005864.
Pan’s above disclosure is incorporated herein by reference. Pan discloses that the subject is APP/PS1 double-transgenic mice used in this study were obtained from the Jackson Laboratory [strain name, B6C3-Tg (APPswe, PSEN1dE9)85Dbo/J; stock number 004462]. [Pg. 1343, col. 2, last para.]. The Jackson Laboratory described the APP/PS1 mice as APP/PS1 are double transgenic mice expressing a chimeric mouse/human amyloid precursor protein (Mo/HuAPP695swe) and a mutant human presenilin 1 (PS1-dE9). Thus, the Pan subject does not carry apoE4. Therefore, claims 20, 21, and 22 are met.
Claim 41 is met because Paolini teaches that patients with Parkinson’s disease, wherein it’s difficult to access area like the brain, contentious administration of drugs by implants is the solution. Paolini teaches that for deep-brain stimulation, Parkinson’s disease drugs are implant in the duodenum, and neuro stimulating electrodes. [Pg. 30, 2nd para.]. Paolini teaches that the extended-release system release he drug for over 4 months. [Pg. 40, 1st para.].
Modified Rejection in view of the Amendment
§ 103 Rejection over Pan and Paolini as evidenced by Reagan-Shaw
Claims 7-9 are rejected under 35 U.S.C. 103 as being unpatentable over X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, “Pan” cited in the IDS dated 07/06/2023) in view of Paolini, Marion S. et al. "Polymers for extended-release administration." Biomedical Microdevices 21, 2 (April 2019): 45 © 2019 Springer Science Business Media, LLC, “Paolini” cited in the PTO-892) as evidenced by Reagan-Shaw S, et al. FASEB J. 2008 Mar;22(3):659-61, “Reagan-Shaw” cited in the PTO-892 dated 09/15/2025).
Pan’s and Paolini’s above disclosures, pages 5-7, are incorporated herein by reference. Pan discloses that benfotiamine is administered at doses of 50 mg/kg/day, 100mg/kg/day and 200mg/kg/day to mice models of human patients. Pan does not disclose that amount of benfotiamine is at least 300 mg, 600 mg or 900 mg in humans.
Reagan-Shaw teaches dose translation from animal to human. [Title]. As explained by Reagan-Shaw, dose translation from mice to human is based on body surface area. [Pg. 660, Abstract].
One of ordinary skill in the art would have been motivated to administer benfotiamine to humans, because Pan teaches benfotiamine works in mice designed to model human Alzheimer’s patients. The person of ordinary skill would have looked to Reagan-Shaw for translating the animal dose to humans, and would have considered it routine practice to extrapolate human dosages from animal dosages.
Based on the formula of Figure 1 and Table 1, 50 mg/kg/day calculates to 243 mg in human (50mg/kg/day x 3/37 = 4.05 mg/kg x 60 (human weight) = 243 mg/day), 100 mg/kg/day calculates to 486 mg/day, and 200 mg/kg/day calculates to 973 mg/day. Thus, the 100 mg/kg/day (486 mg/day) meets claim 7 (at least 300 mg). 200mg/kg/day (973 mg/day) meets the limitation of claims 8 and 9 (at least 600 mg).
§ 103 Rejection over Pan in view of Tapias
Claim 10 is rejected under 35 U.S.C. 103 as being unpatentable over X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, “Pan” cited in the IDS dated 07/06/2023) in view of Paolini, Marion S. et al. "Polymers for extended-release administration." Biomedical Microdevices 21, 2 (April 2019): 45 © 2019 Springer Science Business Media, LLC, “Paolini” cited in the PTO-892) as evidenced by Reagan-Shaw S, et al. FASEB J. 2008 Mar;22(3):659-61, “Reagan-Shaw” cited in the PTO-892) as applied above to claims 7-9, in view of V. Tapias, et al. Human Molecular Genetics, Volume 27, Issue 16, 15 August 2018, Pages 2874–2892, “Tapias” cited in the IDS dated 07/06/2023).
Pan’s and Paolini’s disclosures discussed above on Pages 5-7 are incorporated herein by reference. The combination of Pan, Paolini and Reagan-Shaw teaches treating Alzheimer’s disease in humans with benfotiamine by translating Pan’s dosage amounts from mice to human. For example, Pan’s 200 mg/kg/day calculates to 973 mg/day in human. However, Pan does not disclose that benfotiamine human dose is at least 1200 mg/day.
Tapias teaches that administration of benfotiamine in the amyloid precursor protein (APP)/PS1 mice at a dose of 1250 mg/kg/day rescued cognitive deficits, confers neuroprotection against tau phosphorylation and the generation of neurofibrillary tangles (NFTs), increased lifespan, improved behavior, reduced glycated tau, decreased NFTs and prevented death of motor neurons, [Abstract, and Pg. 2883, col. 1, 2nd para.].
Because Tapias teaches that administration of benfotiamine at a dose of 1250 mg/kg/day exhibited several cognitive benefits in mice, one of ordinary skill in the art would have been motivated to administer benfotiamine at an appropriate dose for humans using Reagan-Shaw’s dose conversion equation as disclosed above (page 8). Therefore, administering a dose of 1250 mg/kg/day to mice calculates to 6081 mg/day in humans (1250mg/kg/day x 3/37 = 101.35 mg/kg/day x 60 (human weight) = 6081 mg/day), which meets the limitation of claim 10 of at least 1200 mg/day.
§ 103 Rejection over Pan in view of Hendrix
Claims 5 and 6 are rejected under 35 U.S.C. 103 as being unpatentable over X. Pan, et al. Brain, Volume 133, Issue 5, May 2010, Pages 1342–1351, “Pan” cited in the IDS dated 07/06/2023) in view of Paolini, Marion S. et al. "Polymers for extended-release administration." Biomedical Microdevices 21, 2 (April 2019): 45 © 2019 Springer Science Business Media, LLC, “Paolini” cited in the PTO-892) further, in view of C. Hendrix (US 20090143433A1, 06/04/2009, “Hendrix” cited in the PTO-892 dated 09/15/2025).
Pan’s and Paolini’s disclosure discussed above on pages 5-7 are incorporated herein by reference. Pan discloses using benfotiamine in treating cognitive impairment, however, Pan does not teach treating mild cognitive impairment or mild dementia.
Hendrix teaches formulations for the “treatment of neurological diseases and cognitive deficiencies, i.e., Alzheimer's Disease, mild cognitive impairment and other types of dementia,” [Abstract], wherein the formulations comprise benfotiamine. [0073]. Hendrix teaches that vitamin B1 “improve[s] cognitive functioning and reduce[s] the levels of biochemical markers for Alzheimer's disease processes,” and “the benfotiamine form of vitamin B1, which is a preferred form of vitamin B1” for use in the treatment of Alzheimer's Disease, mild cognitive impairment and dementia, “has demonstrated significant benefit against excessive glycation and advanced glycation end products” [0057].
Because Pen discloses using benfotiamine in treating cognitive impairment and reports the effectiveness of benfotiamine in treating cognitive impairment, [Pg. 1345, col. 2], and Hendrix teaches benfotiamine for treating Alzheimer's Disease, mild cognitive impairment and dementia [0057], one of ordinary skill in the art would be motivated to use Pen’s benfotiamine for treating mild cognitive impairment and mild dementia, thereby meeting each and every limitation of claims 5 and 6. The person of ordinary skill in the art would have had a reasonable expectation of success because Hendrix teaches benfotiamine improves cognitive functioning and reduces the levels of biochemical markers such as excessive glycation and advanced glycation end products.
Response to Argument
Applicant argues:
None of the references of record, individually or in combination, teach or suggest administering benfotiamine by an extended-release mode as now claimed. Moreover, the present application as filed discloses that administration of benfotiamine by extended release confers a particular advantage for subjects who are incapable or likely incapable of taking one or more daily doses of the compound.
Examiner response:
The rejection is Modified to include Paolini, and independent claim 1 is now rejected over Pan in view of Paolini who provides motivation to the ordinary skilled artisan to formulate Pan’s benfotiamine as an extended-release formulation, see the above 103 Rejections.
Conclusion
Claims 1-10, 17-25, 31 and 41 are rejected. No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
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/M.M.A./Examiner, Art Unit 1622
/JAMES H ALSTRUM-ACEVEDO/Supervisory Patent Examiner, Art Unit 1622