DETAILED ACTION
Status of Application
The Examiner acknowledges receipt of the arguments filed on 7/21/2025.
Claims 1, 2, 4-10, 12-16, 19, 22, 28, 34 and 37-40 are presented for examination on the merits. The following rejections are made.
Response to Applicants’ Arguments
Applicant’s comments filed 7/21/2025 regarding the rejection of claims 1, 2, 4-6, 8-10, 12, 14-16, 19, 22, 28, 34, 38 and 39 made by the Examiner under non-statutory obviousness-type double patenting over 14/715493 in view of 2013/0210808 have been fully considered. As Applicant does not dispute the double patenting rejection, the rejection is MAINTAINED for the reasons of record in the office action mailed on 4/21/2025.
Applicant’s arguments filed 7/21/2025 regarding the rejection of claims 1, 2, 4-6, 8-10, 12, 14-16, 19, 22, 28, 34 and 38 made by the Examiner 35 USC 103 over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302) in view of Yamada et al. (US 2015/0051246), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413) have been fully considered but they are not considered persuasive and are MAINTAINED for the reasons of record in the office action mailed on 4/21/2025.
Applicant’s arguments filed 7/21/2025 regarding the rejection of claims 19 and 22 made by the Examiner 35 USC 103 over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302) in view of Yamada et al. (US 2015/0051246), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413), further in view of Prins et al. (Alzheimers Res Ther, 2014, 6(4), 47) have been fully considered but they are not considered persuasive and are MAINTAINED for the reasons of record in the office action mailed on 4/21/2025.
Applicant’s arguments filed 7/21/2025 regarding the rejection of claims 28 and 39 made by the Examiner 35 USC 103 over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302) in view of Yamada et al. (US 2015/0051246), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413) further in view of Chain et al. (US 2012/0244146) have been fully considered but they are not considered persuasive and are MAINTAINED for the reasons of record in the office action mailed on 4/21/2025.
In response to the 103 rejections, Applicant asserts the following:
Koontz is directed to escalating galantamine dosage and does not tells us that a galantamine dose of 8 mg/day, and even 16 mg/day, would be useful in the treatment of patients with MCI. Essentially Koontz is inconclusive with respect to the potential treatment of MCI with only galantamine. Yamada teaches that combinational therapy including galantamine with a phosphodiesterase 4 inhibitor. It does not teach them separately.
In response to A, the Examiner acknowledges that Koontz is directed to an escalating galantamine treatment regimen. However, the Examiner disputes that Koontz would not suggest a monotherapy as instantly claimed. Koontz teaches that providing only galantamine in an escalating dosage from 0 to 8 mg/day to 16 mg/day to 24 mg/day (by month 3) resulted in substantial improvement in the cognitive ability of MCI patients. Figure 2 shows that the words learned in the galantamine treated group were able to learn more words than those receiving placebo.
Admittedly, Koontz does not teach a treatment where in 4-12 mg of galantamine are administered per day in perpetuity as a sole cognition enhancing agent such that its administration is effective to delay cognitive/functional decline. However, the framework of using galantamine as a sole cognition enhancing agent is described and the amount of administered galantamine described by Koontz is quite close to that claimed. See MPEP 2144.05(I) regarding ranges that are close but do not overlap.
Yamada is cited to provide the claimed dosage profile of galantamine. Yamada teaches that galantamine may be administered at a daily dose of about 2 to about 12 mg, such as 2, 4, 6, 8, 10 or 12 mg, in a preferably at a daily dose of 2, 4, 6 or 8 mg; and galantamine hydrobromide is administered at a daily dose corresponding to 4 or 8 mg of galantamine (see [0112, 0142]). Employing such daily dosages in perpetuity like that described by Koontz would have been within the skill of an ordinary person and would have been expected to yield a method of delaying cognitive/functional decline as taught by Koontz.
While Yamada is directed to a dual therapy, this is not seen as mitigating because the only relevant portion of Yamada relied upon is the dosages of galantamine. The framework of that claimed (i.e. monotherapy of galantamine to treat MCI) is provided by Koontz. Modifying Koontz to use known dosages of galantamine within that described by Koontz would have been obvious. Koontz and Yamada together would obviate a treatment therapy administering a dosage of only galantamine within a dosage of 4-12 mg/day with a reasonable expectation for success in treating MCI. Again, the idea of using only galantamine to treat patients with MCI so as to delay cognitive decline is something plainly described by Koontz. Manipulating the method so identify other treatment modalities would have been within the scope of an ordinarily skilled person and if the manipulation of the prior art found that a treatment method of between 4-12 mg/day of galantamine as a sole cognitive enhancing agent resulted in improvement in MCI patients then this would have been the product of ordinary skill and common sense rather than of innovation.
Maintained Rejections, of Record
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.
Claims 1, 2, 4-6, 8-10, 12, 14-16, 34 and 38 is/are rejected under 35 U.S.C. 103 as being unpatentable over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302; of record) in view of Yamada et al. (US 2015/0051246; of record), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413; of record)
Koontz is directed to the use of galantamine on working memory and global functioning in patients with mild cognitive impairment (MCI) which encompasses patients who are not demented (see instant claim 1). Koontz teaches that the administration of galantamine was initiated at a baseline of 4 mg twice daily. The dose was increased to 8 mg twice daily after one month and to 12 mg twice daily after two months (see page 299). Koontz teaches the method yielded an improvement in the subjects treated with galantamine whereas the placebo group experienced a worsening of symptoms (see page 300). Koontz method administers galantamine as the sole cognition-enhancing agent (see instant claim 1).
Koontz fails to teach their method as administering galantamine in a dose of from 4-12 mg per day. Koontz also fails to teach maintaining or increasing levels of AB42 in CSF, reducing the rate or fall in levels of AB42 in CSF or reducing deposition of amyloid beta in cortex in patients who are not demented but who exhibited a decreased AB42 level in CSF or exhibit increased beta amyloid in cortex.
Yamada teaches a method of treating cognitive impairment such as MCI or delaying the progression from mild cognitive impairment to cognitive impairment associated with Alzheimer's disease in a mammal in need of such treatment, comprising administering to a mammal suffering from cognitive impairment a therapeutically effective amount of a combination of a phosphodiesterase 4 inhibitor and an acetylcholinestase inhibitor (see abstract, [0015, 0035, 0036, 0073-0077, 0079, 0080, 0090, and 0104) wherein the acetylcholinesterase inhibitor include galantamine hydrobromide (see [0090, 0104]) (see instant claim 1). Yamada teaches that "mild cognitive impairment" refers to the symptomatic pre-dementia phase of Alzheimer's disease (see [0019-0021]). As it pertains to patients with MCI who are pre-dementia (i.e. not demented) are those who exhibit a decreased Aβ42 level in CSF (less than 192 pg/ml as measured by the Luminex INNO-BIA AlzBio3 assay) or exhibit increased beta amyloid in cortex the Aβ42 level in CSF as evidenced by Shaw (see page 5 and Table 2). Thus, given that Koontz suggests using only galantamine as a sole active agent to treat/prevent onset of Alzheimer’s, it would have been obvious that such a method would treat patients having decreased AB42 level in CSF or exhibit increased beta amyloid in cortex as indicated by Shaw.
Yamada, like Koontz, teaches that galantamine is administered at a daily dose of about 2 to about 12 mg, such as 2, 4, 6, 8, 10 or 12 mg, in a preferably at a daily dose of 2, 4, 6 or 8 mg; and galantamine hydrobromide is administered at a daily dose corresponding to 4 or 8 mg of galantamine (see [0112, 0142]) (see instant claim 1).
Yamada further disclose that the dose can be readily subdivided into equally effective unit dosage form and galantamine hydrobromide is also formulated in extended release oral tablet form (see [0198, 0246]) (see instant claim 4).
As to claims 5-6, the patients with MCI are those who have a CSF Aβ42 to tau ratio below the discrimination line determined by Aβ42 = 240 + 1.18 x tau and have a ratio of CSF Aβ42 to ptau less than 6.16 (146/32=4.56) as evidenced by Shaw (see Table 2 and Table 5).
As to Claims 9-10, the claims do not require measuring amyloid deposition in brain by PET ligand, but as long as the patient has evidence of amyloid deposition in brain when measured by PET ligands the patients with MCI who are not demented are those having increased beta amyloid in cortex (brain) as described by Shaw et al. (see Table 2 and page 5).
As to claim 38, measuring amyloid deposition in brain is effected by the use of F-fluorodeoxyglucose positron emission tomography and Pittsburgh compound B positron emission tomography as evidenced by Shaw (see page 3).
As to the limitation, “for a period of time such that without such administration cognitive or functional decline would be expected to occur”, Yamada fails to disclose for how long the composition is administered. However, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to administer a suitable amount of galantamine as long as it is necessary for delaying or preventing further cognitive or functional decline since the treatment is intended for delaying the progression from mild cognitive impairment to cognitive impairment associated with Alzheimer's disease as taught by Yamada.
Koontz and Yamada fail to teach measuring CSF Aβ42 levels or cortical amyloid especially several times or three successive times at least 3 months apart or the patient having been assessed by one or more standard tests to have impaired cognitive function on three consecutive months apart.
Shaw teaches a cerebrospinal fluid biomarker signature for Alzheimer’s disease (AD) and MCI (abstract). Shaw teaches that because development of full-blown AD takes place over an approximately 20-year prodromal period and intervention with disease-modifying therapies for AD is likely to be most efficacious before significant neurodegeneration has occurred, there is an urgent need for biomarker-based tests that enable a more accurate and early diagnosis of AD (see page). Shaw teaches that the study includes 819 adult subjects, 55 to 90 years old, who meet entry criteria for a clinical diagnosis of amnestic MCI (n = 397), probable AD (n = 193), or normal cognition (n = 229) and participants receive baseline and periodic physical and neurological examinations and standardized neuropsychological assessments, and provide biological samples (blood, urine, and in a subset, CSF) throughout the study, wherein imaging (magnetic resonance imaging and for a subset, F-fluorodeoxyglucose positron emission tomography and Pittsburgh compound B positron emission tomography) is performed at baseline and at regular intervals thereafter (see p3, Subjects and Methods). Shaw further disclose that Api-42, t-tau, and p-taul81p were measured in each of the 416 CSF ADNI baseline aliquots using the multiplex xMAP Luminex platform (Luminex Corp, Austin, TX) with Innogenetics (INNO-BIA AlzBio3; Ghent, Belgium; for research use-only reagents) immunoassay kit-based reagents (see p4 para 2). Shaw indicates that patients with MCI exhibit a decreased Aβ42 level in CSF (less than 192 pg/ml as measured by the Luminex INNO-BIA AlzBio3 assay) compared to normal (NC) or exhibit increased beta amyloid in cortex the Aβ42 level in CSF (see Table 2 and p5, para 1) and patients with MCI are those who have a CSF Aβ42 to tau ratio below the discrimination line determined by Aβ42 = 240 + 1.18 x tau and have a ratio of CSF Aβ42 to ptau less than 6.16 (146/32=4.56) (see Table 2 and Table 5). In addition, Shaw disclose that Api-42 average concentrations, on the other hand, decrease when comparing normal (NC) with MCI, then decrease further in comparing MCI with AD (see p4, Results).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to measure CSF Aβ42 levels or cortical amyloid or assess decline in cognitive function several times or three successive measurements at least 3 months apart for determining whether the patient has AD or MCI since CSF Aβ42 levels or cortical amyloid were well known markers for distinguishing AD from MCI and normal subjects. The skilled artisan would have been motivated to measure those makers several times to obtain accurate diagnosis for the status of the patients on the reasonable expectation that decrease in CSF Aβ42 levels or increase in cortical amyloid or declined cognitive function over the period of time would provide predictive value for higher risk to progression from normal to MCI and MCI to AD. In addition, Shaw teaches that such biomarker-based tests enable more accurate and early diagnosis and intervention with disease-modifying therapies for AD is likely to be most efficacious before significant neurodegeneration has occurred. Thus, one of ordinary skill in the art would have been motivated to use the composition comprising galantamine for treating those patients who had been determined to have higher risk of AD based on CSF Aβ42 levels or cortical amyloid as taught by Koontz and Yamada.
Regarding the requirement that the instantly claimed limitation of maintaining or increasing level of Aβ42 in CSF, reducing deposition of amyloid beta in cortex, slowing the deposition of beta amyloid in brain, or clearing beta amyloid from brain, the prior art teaches administering a therapeutically acceptable dose of the same compound to the same patients (e.g., patients with MCI who are not demented, but exhibit a decreased Aβ42 level in CSF or exhibit increased beta amyloid in cortex as evidenced by Shaw), these claimed intended results would necessarily occur given the substantial overlap in method steps.
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was filed, as evidenced by the references, especially in absence of evidence to the contrary.
Claims 19 and 22 are rejected under 35 U.S.C. 103 as being unpatentable over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302) in view of Yamada et al. (US 2015/0051246; of record), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413; of record) as applied to claims 1, 2, 4-6, 8-10, 12, 14-16, 34 and 38 above, and further in view of Prins et al. (Alzheimers Res Ther, 2014, 6(4), 47; of record).
Koontz and Yamada do not specifically teach that the patient has medial temporal lobe, paralimbic, and/or temporoparietal lobe atrophy on structural MR1 or the patient has been determined to have APOε4 allele.
Prins teaches that patients with MCI who are pre-dementia (i.e. not demented) encompass those having medial temporal lobe, paralimbic, and/or temporoparietal lobe atrophy on structural MR1. Prins teaches that the degree and rate of medial temporal lobe and brain atrophy in individuals with MCI is greater than that in normal controls and less than that in patients with AD when measured on magnetic resonance imaging (MRI) (see p2, col 1 para 2) and further teaches that in MCI subjects a lower brain or hippocampal volume or a higher rate of brain or hippocampal atrophy is predictive of progression of MCI to AD and the effect of galantamine (compared with placebo) on the rate of total brain and hippocampal atrophy was assessed using serial MRI in individuals with MCI (see p2, col 1, para 2 and 4). Regarding claim 22, it was known in the art that the APOε4 allele is the most robust genetic risk factor for sporadic AD as evidenced by Shaw (see p6, para 2). Prins also teaches that in a subset of MCI patients who participated in the Gal-Int-11 trial and underwent MRI at baseline and at 24 months, MCI patients who received galantamine showed lower whole brain atrophy rates (reduction of decrease in brain volume) compared with those treated with placebo and in subsequent stratified analyses, this difference was only present in patients who carried an APOε4 allele (see p4, table 3 and col 2, Discussion section). Prins found that galantamine only lowered the rate of brain atrophy in MCI patients who were APOε4 carriers and compared with noncarriers, these MCI patients are more likely to have underlying AD pathology; that is, they are more likely to classify as prodromal AD according to the Albert criteria since APOε4 positivity in MCI has been found to be associated with amyloid positron emission tomography (PET) positivity, and with the AD biomarker profile in cerebrospinal fluid (see p5, col 1, para 4). Thus, it would have been obvious to use the composition of Yamada for MCI patients who have medial temporal lobe, paralimbic, and/or temporoparietal lobe atrophy on structural MR1 and/or have been determined to have the APOε4 isoform with reasonable expectation of success because Yamada already teaches the composition comprising galantamine is useful for treating MCI patients or delaying the progression from mild cognitive impairment to cognitive impairment associated with Alzheimer's disease and Prins teaches that galantamine only lowered the rate of brain atrophy in MCI patients who were APOε4 carriers.
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was filed, as evidenced by the references, especially in absence of evidence to the contrary.
Claims 28 and 39 are rejected under 35 U.S.C. 103 as being unpatentable over Koontz et al. (Am J Alzheimers Dis Other Demen, 2005, 20(5), 295-302) in view of Yamada et al. (US 2015/0051246; of record), evidenced by or in view of Shaw et al. (Ann Neurol 2009, 65(4), 403-413; of record) as applied to claims 1, 2, 4-6, 8-10, 12, 14-16, 34 and 38 above, and further in view of Chain et al. (US 2012/0244146; of record).
Koontz and Yamada do not specifically disclose co-administering agents that promote the clearance of Ap deposit such as solaneszumab and gantenerumab as recited in claims 28 and 39.
Chain teaches methods of promoting clearance of aggregates from the brain and treating Alzheimer's and other tauopathies such as mild cognitive impairment comprising administering antibodies that have binding specificity to abnormal forms of tau protein (Abstract, claim 21, and [0060]). Chain further teaches administration of one or more antibodies specific for the neoepitope generated by cleavage of APP, including antibodies specific for Ap species, such as solaneszumab and gantenerumab for treating Alzheimer's disease and MCI (see [0278] and claims 1 and 38-40).
Therefore, it would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to co-administer antibodies specific for Ap species such as solaneszumab or gantenerumab with the composition comprising galantamine taught by US2015/0051246 for treating MCI patients since the antibodies were known to be useful for treating MCI by clearing aggregates from the brain as evidenced by Chain. See MPEP 2144.06(I) which states that “[I]t is prima facie obvious to combine two compositions each of which is taught by the prior art to be useful for the same purpose, in order to form a third composition to be used for the very same purpose.... [T]he idea of combining them flows logically from there having been individually taught in the prior art.”
Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was filed, as evidenced by the references, especially in absence of evidence to the contrary.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
Claims 1-2, 4-10, 12-16, 19, 22, 28, 34, and 37-39 are provisionally rejected on the ground of nonstatutory obviousness-type double patenting as being unpatentable over claims 1, 4-6, and 8-54 of copending application 14/715493 in view of US2013/0210808.
Although the conflicting claims are not identical, they are not patentably distinct from each other because the claims of ‘493 application are drawn to a method of administering a prodrug of galantamine to the same patient as claimed. While the claims of 493 does not specifically galantamine, the compounds disclosed in ‘493 application are prodrugs of galantamine which would be converted into galantamine in vivo as evidenced by US2013/0210808 (see abstract, [0025], [0123] and Fig. 1). Thus, one of ordinary skill in the art would have been motivated to use galantamine for the same patient as recited in 493 application on the reasonable expectation that both compounds would provide similar effects for treating the same MCI patients.
Conclusion
THIS ACTION IS MADE FINAL. 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 extension fee 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KYLE A PURDY whose telephone number is (571)270-3504. The examiner can normally be reached from 9AM to 5PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Bethany Barham, can be reached on 571-272-6175. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/KYLE A PURDY/Primary Examiner, Art Unit 1611
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