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 .
Claim Rejections - 35 USC § 103
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
Claim(s) 1, 13-18, 20, 22, 30 and 35-38 are rejected under 35 U.S.C. 103 as being unpatentable over Kennedy et al (WO 2018/200736 A2) in view of Schor et al (JP S58-174311 (a reference disclosed in IDS of 10/28/2024) and its English equivalent US 4,389,393) (with (i) Guo (“Lactose in Pharmaceutical Applications”, Drug Development & Delivery, vol.4 (5) (June 2004), obtained from the website: https://drug-dev.com/lactose-in-pharmaceutical-applications/ ), which is being cited here merely to support the Examiner’s assertion that the most common form of lactose used in pharmaceutical formulation is crystalline a-lactose monohydrate; and (ii) “Dietary Reference Intakes for Calcium and Vitamin D” (Institute of Medicine of the National Academies, November 2010, pg.1-4, obtained from the website: https://nap.nationalacademies.org/resource/13050/Vitamin-D-and-Calcium-2010-Report-Brief.pdf), which is being cited here merely to support the Examiner’s assertion that the daily dietary value of calcium ranges from 700-1,300 mg/day for children and adults).
For the discussion below, US 4,389,393 (English equivalent of JP S58-174311) is being used here instead of the Japanese document.
Kennedy teaches (claim 1) a method of extending lifespan in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of berberine, a vitamin A compound and a-ketoglutarate (“AKG”). In claim 3, Kennedy teaches that the berberine, the vitamin A compound and AKG can be administered to the subject separately. Thus, it would have been obvious to one skilled in the art to administer the AKG separately with a reasonable expectation of success. In claim 7, Kennedy teaches that the AKG is formulated as a calcium salt. Thus, Kennedy teaches instant calcium alpha-ketoglutarate. Kennedy further teaches ([00236]) that a pharmaceutical composition comprising any of the active agents described in the reference may be formulated for sustained or slow release (also called controlled release) and teaches that the sustained release formulations may be dispersed in a carrier matrix. Thus, it would have been obvious to one skilled in the art to have a sustained release formulation comprising AKG calcium salt (instant calcium alpha-ketoglutarate) dispersed in a carrier matrix (a controlled-release matrix) with a reasonable expectation of success.
With respect to instant controlled-release matrix comprising a first HPMC with Mn in the range from about 68,000 to about 95,000, and a second HPMC with Mn in the range from about 115,000 to about 150,000, Kennedy does not provide any detail as to the carrier matrix for its AKG calcium salt. Schor et al teaches (col.2, lines 59-68) a carrier base for use with high dosage medicaments in sustained release dosage forms comprising a high viscosity grade HPMC having a number average molecular weight above 50,000 and a methoxyl content of 16-24 wt.% wherein the carrier base constitutes less than about a third of the sustained release dosage form. Schor teaches (col.4, lines 1-6) that the sustained release drug forms containing the high viscosity grade HPMC of its invention give a stable, steady reproducible release of the active medicament (Schor teaches (col.4, lines 29-35) that the active ingredient can be of any type of medication which can be administered orally to transmit the active medicament into the gastrointestinal tract and into the blood, fluids and tissues of the body without excessive peak concentrations occurring). Schor further teaches (col.4, lines 7-15) that the HPMC having a Mn above 50,000 and a methoxyl content of 16-24 wt.% can be used in admixture in all proportions with other HPMC of the same structure with a higher or a lower but above 50,000 Mn. As an example for such admixture, Schor gives an admixture of Methocel K4M (Mn of 89,000, methoxyl content 19-24 wt.%) and Methocel K15M (Mn of 124,000, methoxy content 19-24 wt.%) (see Col.2, lines 19-30 and Examples 9, 13, 14, 26 and 27). It would have been obvious to one skilled in the art to use a mixture of Methocel K4M (instant first HPMC having Mn 89,000) and Methocel K15M (instant second HPMC having Mn 124,000) in Kennedy’s sustained formulation as a carrier matrix for the calcium alpha ketoglutarate with a reasonable expectation of providing a stable, steady reproducible release of the calcium alpha ketoglutarate. Thus, Kennedy in view of Schor renders obvious instant controlled-release matrix of claim 1.
With respect to instant diluent, Kennedy teaches ([00230]) that when its pharmaceutical composition containing its active agent is prepared for oral administration, the composition may contain excipients, such as cellulose preparations, which examples include microcrystalline cellulose. It would have been obvious to one skilled in the art to further include microcrystalline cellulose (instant diluent of claim 14) in Kennedy’s pharmaceutical composition for oral administration with a reasonable expectation of success.
Thus, Kennedy in view of Schor renders obvious instant claims 1 and 14.
With respect to instant claims 13, 16-18, 20 and 22, as discussed above, Kennedy teaches ([0230]-[0232]) that when its pharmaceutical composition containing its active agent is prepared for oral administration, the composition may contain excipients, and as suitable excipients, Kennedy teaches cellulose preparations (such as microcrystalline cellulose as mentioned above), disintegrating agents (as claimed in instant claim 18), lubricants, such as magnesium stearate (as claimed in instant claims 16 and 17), and sugar solutions (instant sweetener of claim 20). Kennedy further teaches ([0069]) the use of waxes (as claimed in instant claim 22). Based on Kennedy’s teaching, it would have been obvious to one skilled in the art to use these excipients as taught by Kennedy in its pharmaceutical composition for oral administration with a reasonable expectation of success. Thus, Kennedy in view of Schor renders obvious instant claims 13, 16-18, 20 and 22.
With respect to instant claim 15, Kennedy also includes ([0230]) lactose (as a filler) among examples for the excipients that can be used in its pharmaceutical compositions containing active agents for oral use, and as evidenced by Guo (see under “GENERAL PROPERTIES OF LACTOSE AS AN EXCIPIENT”), the most common form of lactose used in pharmaceutical formulation is crystalline a-lactose monohydrate. It would have been obvious to one skilled in the art to use crystalline a-lactose monohydrate in Kennedy’s pharmaceutical composition as one of excipients with a reasonable expectation of success. Thus, Kennedy in view of Schor renders obvious instant claim 15.
With respect to instant claim 30, Kennedy teaches ([00103]) that its calcium a-ketoglutarate can be in a mono-hydrate form. Thus, Kennedy in view of Schor renders obvious instant claim 30.
With respect to instant claims 35 and 36, Kennedy teaches (claims 45-46) that its composition can be orally administered in a tablet form. Kennedy also teaches (claims 40, 44 and 47) that the therapeutically effective amount of calcium a-ketoglutarate is 350-750 mg. It would have been obvious to one skilled in the art to make Kennedy’s composition containing 350-750 mg of calcium a-ketoglutarate monohydrate, a mixture of Methocel K4M (instant first HPMC having Mn 89,000) and Methocel K15M (instant second HPMC having Mn 124,000) as the carrier matrix for calcium a-ketoglutarate monohydrate, and excipients including microcrystalline cellulose (instant diluent) into a tablet form (instant unit dose configured for oral administration as recited in claim 36) for oral administration with a reasonable expectation of success. Furthermore, under the general guideline given by Kennedy for the therapeutically effective amount (350-750 mg) of a-ketoglutarate, instant amount (525mg) for the calcium alpha-ketoglutarate monohydrate would have been obvious to one skilled in the art before the effective filing date of the claimed invention since it has been held that where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. In re Aller, 105 USPQ 23. Thus, Kennedy in view of Schor renders obvious instant claims 35 and 36.
With respect to instant claim 37, as discussed above, Kenney teaches that the therapeutically effective amount of a-ketoglutarate is 350-750 mg. Such range falls within instant range 250-1000 mg of claim 37 and thus teaches instant range. Thus, Kennedy in view of Schor renders obvious instant claim 37.
With respect to instant claim 38, Kennedy does not tech instant limitation of claim 38. As evidenced by “Dietary Reference Intakes for Calcium and Vitamin D” (see Table on pg.2), the daily dietary value of calcium ranges from 700-1,300 mg/day for children and adults. About 10% of such amount would be 70-130 mg/day. Since Kennedy teaches (claims 40, 44 and 47) that the therapeutically effective amount of calcium a-ketoglutarate is 350-750 mg, and since calcium comprises 21.7% by weight (as calculated by the Examiner using molecular weight of calcium a-ketoglutarate which is 184 g/mol and atomic weight of calcium which is 40 g/mol) of the calcium a-ketoglutarate, this gives a range of calcium amount contained in 350-750 mg of calcium a-ketoglutarate to be 76-163 mg/day. Such amount exceeds 70-130 mg/day (which is 10% of the daily dietary value of calcium). Thus, Kennedy teaches instant limitation of claim 38 as to the unit dose comprising at least about 10% of the daily dietary value of calcium.
Thus, Kennedy in view of Schor renders obvious instant claim 38.
Claim(s) 6 and 24 are rejected under 35 U.S.C. 103 as being unpatentable over Kennedy et al (WO 2018/200736 A2) in view of Schor et al (JP S58-174311 and its English equivalent US 4,389,393), as applied to claim 1 above, and further in view of Byrd (US 2005/0106246 A1).
With respect to instant claim 6, Kennedy does not explicitly teach instant amount of calcium alpha-ketoglutarate (about 30-65 wt.%) based on the total weight of the composition. Byrd teaches (claim 1) a controlled release oral dosage formulation of arginine a-ketoglutarate, and such formulation contains 50-70% of arginine a-ketoglutarate and 30-70% of excipient material which can include HPMC based on the total weight of the composition. Byrd teaches that such formulation is characterized by releasing the arginine a-ketoglutarate in a manner so as to increase a period of time over which a therapeutic level of arginine a-ketoglutarate is maintained as compared to a quick release formulation. Thus, although Byrd does not teach calcium a-ketoglutarate, it does teach a sustained release formulation of a-ketoglutarate. Since Kennedy also seeks a sustained release formulation of a-ketoglutarate, it would have been obvious to one skilled in the art to take Byrd’s teaching and use about 50-70 wt.% of calcium a-ketoglutarate in Kennedy’s formulation with a reasonable expectation of releasing the calcium a-ketoglutarate in a manner so as to increase a period of time over which a therapeutic level of calcium a-ketoglutarate is maintained as compared to a quick release formulation. The range 50-70 wt.% for the calcium a-ketoglutarate overlaps with instant range of claim 6 (30-65 wt.%), thus rendering instant range prima facie obvious. In the case “where the [claimed] ranges overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness would exist which may be overcome by a showing of unexpected results, In re Wertheim, 541 F.2d 257, 191 USPQ 90 (CCPA 1976). Thus, Kennedy in view of Schor, and further in view of Byrd renders obvious instant claim 6.
With respect to instant claim 24, Byrd teaches (claim 25) that the releasing of a-ketoglutarate is at a rate of about 25% or less per hour after an initial release rate within 30 minutes following administration as compared to a quick release formulation. The release rate of about 25% or less teaches instant range of about 90% or less. Thus, Kennedy in view of Schor, and further in view of Byrd renders obvious instant claim 24 (besides, since Kennedy in view of Schor teaches instant composition comprising calcium alpha-ketoglutarate, instant diluent and instant controlled-release matrix as described in instant claim 1, it is the Examiner’s position that such composition would inherently satisfy instant limitation of claim 24).
Claim(s) 19 is rejected under 35 U.S.C. 103 as being unpatentable over Kennedy et al (WO 2018/200736 A2) in view of Schor et al (JP S58-174311 and its English equivalent US 4,389,393), as applied to claim 18 above, and further in view of Bortz (WO 2014/197250 A1).
With respect to instant claim 19, Kennedy teaches the use of disintegrating agent, which examples include crosslinked carmellose sodium, sodium alginate and agar, for its orally administered formulation ([00230]), but Kennedy does not teach instant silicon dioxide. However, as evidenced by Bortz ([0053]), those disintegrants taught by Kennedy are known in the art as equivalent to (or interchangeably used with) colloidal silicon dioxide. It would have been obvious to one skilled in the art to use colloidal silicon dioxide as a disintegrating agent in Kennedy’s composition with a reasonable expectation of success. Thus, Kennedy in view of Schor, and further in view of Bortz renders obvious instant claim 19.
Response to Arguments
Applicant did not present any argument with respect to the pending 103 rejections other than stating that “[i]n view of the foregoing amendments, it is submitted that the instant application is in condition for continued examination and allowance.” However, for the reasons already explained above, applicant’s amendment (in claims 1 and 35) does not put instant application in condition for allowance, and instant 103 rejections over Kennedy in view of Schor still stand.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SIN J. LEE whose telephone number is (571)272-1333. The examiner can normally be reached on M-F 9 am-5:30pm.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Brian Kwon can be reached on 571-272-0581. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SIN J LEE/
Primary Examiner, Art Unit 1613
March 7, 2026