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 .
DETAILED ACTION
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on May 19, 2025 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed April 18, 2025 and May 19, 2025 is acknowledged. Claim 21 is cancelled. Claims 1-20 and 22 are pending in this application and under examination in this office action.
4. Applicant’s arguments filed on April 18, 2025 and May 19, 2025 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Maintained
In view of the amendment filed on April 18, 2025 and May 19, 2025, the following rejections are maintained.
Claim Rejections - 35 USC § 103
5. 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 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 1-20 and 22 stand rejected under 35 U.S.C. 103 as being unpatentable over Mercken et al. (US10766953) in view of Griswold-Prenner et al. (US9051367) and Adolfsson et al. (US10836817). The rejection is maintained for the reasons made of record and the reasons set forth below.
Claims 1-20 and 22 as amended are drawn to methods of reducing total cerebrospinal fluid p217+Tau (CSF-p217+Tau), free CSF-p217+Tau, total CSF-Tau, CSF-p181tau in a human subject in need of treatment of Alzheimer’s disease (AD) including early AD, MCI due to AD or mild to moderate AD, comprising administering to the human subject a composition comprising a pharmaceutically acceptable carrier and about 10-60mg/kg per dose of a monoclonal antibody comprising HCDRs1-3 comprising or consisting of the amino acid sequences of SEQ ID NOs: 1-3 respectively and LCDRs1-3 comprising or consisting of the amino acid sequences of SEQ Id NOs: 13-15 respectively.
Response to Arguments
On p. 7-12 of the response, Applicant argues that i) Mercken does not disclose the claimed range of about 10-60mg/kg per dose; ii) a skilled artisan would not apply the dosing in Griswold-Prenner and Adolfsson to Mercken because the epitopes for anti-tau antibodies disclosed by Griswold-Prenner and Adolfsson are different from the claimed anti-Tau antibody or the anti-Tau antibody disclosed by Mercken, which would not be expected to have the same efficacy and cites Courade et al. (Acta Neuropathologica, 2018; 136:729-745) in support of the arguments; iii) the claimed dosing range cannot be achieved by routine optimization because the dose ranges disclosed by Griswold-Prenner and Adolfsson is extremely broad and would not be obvious to try or optimize. Applicant further cites KSR Intl. Co.v. Teleflex, Inc., MPEP2144.05II.C., Genetics, Inst., LLC v. Novartis Vaccines & Diagnostics, Inc., MPEP2144.05II.D.in support of the arguments; iv) the claimed dosing range is critical because 1) the claimed antibody at the claimed dose range of 10-60mg/kg in human resulted in about 70% reduction from baseline in total p217+tau in CSF(see paragraphs 5-6 of the Li’s declaration) and 2) the active p217+tau clearance was confirmed in patients with prodromal or mild AD at doses of 15mg/kg and 30mg/kg (see paragraph 7 of the Li’s declaration) and such a reduction CSF total p217+tau cannot find at a dose below 10mg/kg (see Figure B).
Applicant's arguments have been fully considered but they are not found persuasive. Contrary to Applicant's arguments, the examiner asserts that based on MPEP §2141, MPEP2141-I, rationales identified by the Court in KSR (KSR International Co. v. Teleflex Inc. (KSR), 550 U.S. 398, 82 USPQ2d 1385 (2007)), MPEP2141-II, the basic factual inquires of Graham v. John Deere Co.(Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966)),and MPEP §2141.01-2147.03, the cited references do render the claimed invention obvious because:
i. Mercken teaches a method of treating tauopathies including AD, MCI due to AD, early AD, mild to moderate AD in a subject in need thereof including a human subject (see col.12, lines 22-23) using the same material (i.e. the same monoclonal anti-PHF-tau antibody) and the same active step (i.e. administering including intravenously administering to the human subject) in the same patient population (i.e. a human/patient suffering from AD, MCI due to AD, early AD, mild to moderate AD) (see the sequence alignment; col.4, lines 1-27; col. 4, line 49-col. 5, line 7; col. 5, lines 18-24; col. 12, line 63-col.13, line 14; col.14-17, tables 1-4; col.18, line 64-col.22, line 67; col. 30, line 1-col. 32, line 18; col. 32, line 22-41; col.32, lines 58-col.33, line 35; col. 39, lines 4-15, col. 51, line 1-col.53, line 67, Example 9; claims 31-39).
Mercken also teaches 20mg/kg per dose (within the claimed ranges of about 10-60mg/kg, 10-40mg/kg, 20-60mg/kg, about 20mg/kg per dose) (see col. 53, lines 12-17; col. 54, table 17; col. 27, lines 32-40).
Even if the 20mg/kg per dose disclosed in Example 9 of Mercken is only for mice, based on the conversion ratio from animal doses to human doses known in the art or by the FDA guidance (multiply animal dose by 0.08), the human dose converted from the 20mg/kg for mice is equal to 1.6mg/kg, which is effective to treat tauopathies including AD, MCI due to AD, early AD, mild to moderate AD and to clear the CSF total p217+Tau, which is also acknowledged by Applicant (see Figures A-B of the Dr.Li’s declaration) because as shown in Figures A-B of the DR. Li’s declaration, 1mg/kg or 3mg/kg is effective to reduce free CSF p217+Tau (i.e. ~60%,~70% change from baseline) or total CSF p217+Tau (~45%, ~58% change from baseline), which is also supported by the data shown in the figures 8-15 of the instant specification.
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ii. Even if the dose disclosed by Mercken is not identical to the claimed dose or within the claimed ranges, Griswold-Prenner and Adolfsson teach the use of an anti-tau antibody at dose ranges including the claimed doses or the claimed ranges for treatment of tauopathies including AD.
Both Mercken and secondary references: Griswold-Prenner and Adolfsson teach the use of an anti-Tau antibody using a dose range that is either narrower or broader is effective to treat tauopathies including AD and reduce CSF tau protein in claims and examples of these issued patents (see claim 3 in Mercken and claim 14 in Adolfsson).
Applicant’s arguments related to different epitopes are irrelevant to the combined teachings of Mercken with Griswold-Prenner and Adolfsson because the anti-PHF-tau monoclonal antibody disclosed by Mercken is identical to the claimed anti-Tau antibody.
Griswold-Prenner teaches dose ranges and regimens including 0.0001-100mg/kg per dose, 1-10mg/kg, 15mg/kg, 30mg/kg on alternative days or 60mg/kg weekly, once per every two weeks or once a month, once every 3-6 months or over a period such as at least six months, which are within the ranges recited in claims 1-4, 12-15 and 17-18 (see col. 13, lines 45-col. 16, line 15; col. 16, lines 28-52; col.43, line 56 to col. 44, line 5).
Adolfsson teaches a dose range of 1pg/kg-15mg/kg; 1pg/kg-100mg/kg, 0.05-10mg/kg, 10mg/kg per dose and different frequencies regimens including one or more separate administration over several days or longer or every week or every three weeks (see col. 78, lines 11-46; col.9, lines19-24; col. 9, line 38-col. 10, line 12; col. 10, lines 24-67; col. 11, lines 1-40; col. 15, line 51 to col. 16, line 8; col. 22, lines 1-42; col. 22, lines 55-67; col. 69, line 5-col. 70, line 67; col. 71, lines 16-col. 75, line 20).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known dose ranges and regimens and technique disclosed by Griswold-Prenner and Adolfsson to the Mercken’s method and yield the predictable result of treating tauopathies including AD and reducing CSF tau protein in the subject in need thereof because the dose ranges disclosed in Mercken, Griswold-Prenner and Adolfsson have been shown to be effective to treat tauopathies including AD and reduce CSF tau protein including total/free CSF p217+Tau and CSF p181Tau.
iii. The Dr. Li’s declaration under 37 CFR 1.132 filed 11/21/2024 or 05/19/2025 is insufficient to overcome the rejection of claims1-20 and 22 based upon Mercken et al. (US10766953) in view of Griswold-Prenner et al. (US9051367) and Adolfsson et al. (US10836817) under 35 U.S.C. 103 as set forth in the last Office action because: It include(s) statements which amount to an affirmation that the affiant has never seen the claimed significant reduction in CSF free 217+tau and significant reduction in CSF total p217+tau (i.e. about 70% from baseline) before when administration of the claimed monoclonal antibody at 10, 30 or 60 or 10-60mg/kg (paragraphs 6-7). This is not relevant to the issue of nonobviousness of the claimed subject matter and provides no objective evidence thereof. See MPEP § 716.
Based on Applicant’s own admission and data shown in Figures A-B, the percentage change from baseline for free CSF p217+Tau are
1mg/kg 3mg/kg 10mg/kg 30mg/kg 60mg/kg
% free CSF p217+Tau ~60% ~70% ~85% ~90% ~95%
% total CSF p217+Tau ~45% ~58% ~70% ~68% ~71%
The differences of the percentage change from baseline for free CSF p217+Tau and total CSF p217+Tau between the dose of 1mg/kg or 3mg/kg and the claimed dose range of 10mg/kg-60mg/kg are not surprising or unexpected because the differences are dramatical; Rather there is a dose dependent relationship between the dose and the effect, a higher dose is more effective than a loser dose, which is predicted and expected and is known in routine practice in the art.
Note that “Any differences between the claimed invention and the prior art may be expected to result in some differences in properties. The issue is whether the properties differ to such an extent that the difference is really unexpected”. See: MPEP §716.02.
“Evidence of unexpected results must be weighed against evidence supporting prima facie obviousness in making a final determination of the obviousness of the claimed invention. In re May, 574 F.2d 1082, 197 USPQ 601 (CCPA 1978)”. See MPEP 716.02(c)-I.
“A greater than expected result is an evidentiary factor pertinent to the legal conclusion of obviousness ... of the claims at issue.” In re Corkill, 711 F.2d 1496, 226 USPQ 1005 (Fed. Cir. 1985). See MPEP 716.02(a)-I.
In this case, even if Mercken does not teach a dose range that is exactly identical to the claimed ranges of about 10-60mg/kg,10-40mg/kg, 20-60mg/kg, 40-60mg/kg, about 10, 15, 25, 30, 35, 40, 45, 50,55, 60mg/kg or any value in between per dose recited in claims 1-4 and 12-15, Griswold-Prenner and Adolfsson teach these limitations and provide motivation and an expectation of success in using the claimed dose range in the Mercken’s method because Griswold-Prenner teaches dose ranges and regimens including 0.0001-100mg/kg per dose, 1-10mg/kg, 15mg/kg, 30mg/kg on alternative days or 60mg/kg weekly, once per every two weeks or once a month, once every 3-6 months or over a period such as at least six months, which are within the ranges recited in claims 1-4, 12-15 and 17-18 and Adolfsson teaches a dose range of 1pg/kg-15mg/kg; 1pg/kg-100mg/kg, 0.05-10mg/kg, 10mg/kg per dose and different frequencies regimens including one or more separate administration over several days or longer or every week or every three weeks for treating tauopathies including AD and reducing CSF tau protein.
A person of ordinary skill in the art would have recognized that selecting and applying the known dose ranges and regimens and the known technique disclosed by Griswold-Prenner and Adolfsson to the Mercken’s method would have yielded the predictable result of treating tauopathies including AD, MCI due to AD, early AD, mild to moderate AD and reducing CSF tau protein including reducing total CSF-p217+Tau, free CSF-p217+Tau, total CSF-Tau, CSF-p181tau, and resulted in an improved method.
Using the known dose ranges and regimens in the Mercken’s method would treat tauopathies including AD, MCI due to AD, early AD, mild to moderate AD and reduce CSF tau protein including reducing total CSF-p217+Tau, free CSF-p217+Tau, total CSF-Tau, CSF-p181tau, and expand application of the Mercken’s method, and would increase patient’s satisfaction with treatment of tauopathies using an anti-tau antibody because the claimed dose ranges and regimens have been used for treatment of tauopathies including AD, MCI due to AD, early AD, mild to moderate AD and reducing CSF tau protein.
The claimed method requires a dose range of 10-60mg/kg,10-40mg/kg, about 20-60mg/kg, about 40-60mg/kg, about 10, 15, 25, 30, 35, 40, 45, 50,55, 60mg/kg or any value in between per dose, which overlaps with the range of Griswold-Prenner and Adolfsson because Griswold-Prenne teaches a dose range of 0.0001-100mg/kg per dose, 1-10mg/kg, 15mg/kg, 30mg/kg on alternative days or 60mg/kg weekly, once per every two weeks or once a month, once every 3-6 months or over a period such as at least six months, and Adolfsson teaches a dose range of 1pg/kg-15mg/kg; 1pg/kg-100mg/kg, 0.05-10mg/kg or 10mg/kg per dose and different frequencies regimens including one or more separate administration over several days or longer or every week or every three weeks. Because the claimed range overlaps with the range disclosed by the prior art, a prima facie case of obviousness exists.
Thus, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to select and apply the known dose ranges and regimens and the known technique disclosed by Griswold-Prenner and Adolfsson to the Mercken’s method and yield the predictable result of treating tauopathies including AD, MCI due to AD, early AD, mild to moderate AD and reducing CSF tau protein in the subject in need thereof.
Further, routine optimization of Mercken’s, Griswold-Prenner’s and Adolfsson’s dose ranges would have led to the claimed range of 10-60mg/kg,10-40mg/kg, about 20-60mg/kg, about 40-60mg/kg, about 10, 15, 25, 30, 35, 40, 45, 50,55, 60mg/kg or any value in between per dose because Griswold-Prenne teaches a dose range of 0.0001-100mg/kg per dose, 1-10mg/kg, 15mg/kg, 30mg/kg on alternative days or 60mg/kg weekly, once per every two weeks or once a month, once every 3-6 months or over a period such as at least six months, and Adolfsson teaches a dose range of 1pg/kg-15mg/kg; 1pg/kg-100mg/kg, 0.05-10mg/kg, 10mg/kg per dose and different frequencies regimens including one or more separate administration over several days or longer or every week or every three weeks achieve the reduction of CSF tau protein desired in the Mercken’s method. The person of ordinary skill in the art would have found it obvious to optimize within the range taught by Griswold-Prenner and Adolfsson because Griswold-Prenner and Adolfsson teach that this entire range reduces CSF tau protein levels in patients with tauopathies including AD, MCI due to AD, early AD, mild to moderate AD, and also teach how to optimize the dose ranges and regimens.
Note that “[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, 105USPQ 233, 235 (CCPA 1955)” See MPEP 2144.05-II.
“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.” see also Peterson, 315 F.3d at 1330, 65 USPQ2d at 1382; In re Hoeschele, 406 F.2d 1403, 160 USPQ 809 (CCPA 1969); Merck & Co. Inc. v. Biocraft Laboratories Inc., 874 F.2d 804, 10 USPQ2d 1843 (Fed. Cir.), cert.denied, 493 U.S. 975 (1989); In re Kulling, 897 F.2d 1147, 14 USPQ2d 1056 (Fed. Cir. 1990); and In re Geisler, 116 F.3d 1465, 43 USPQ2d 1362 (Fed. Cir. 1997). See MPEP § 2144.05.
In view of the foregoing, when all of the evidence is considered, the totality of the rebuttal evidence of nonobviousness fails to outweigh the evidence of obviousness.
Accordingly, the rejection of claims 1-20 and 22 under 35 U.S.C. 103 as being unpatentable over Mercken (US10766953) in view of Griswold-Prenner (US9051367) and Adolfsson (US10836817) is maintained.
Double Patenting
6. 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 filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual 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/apply/applying-online/eterminal-disclaimer.
Claims 1-20 and 22 stand provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 3-22 of copending Application No. 17509910 in view of Mercken et al. (US10766953), Griswold-Prenner et al. (US9051367) and Adolfsson et al. (US10836817). The rejection is maintained for the reasons made of record and the reasons set forth below.
On p. 13 of the response, Applicant argues that Applicant would consider filing a terminal disclaimer upon indication of allowable subject matter.
Applicant's arguments have been fully considered but they are not found persuasive. Application No. 17509910 (the ‘910 Application) claims a method of treating a tauopathy using the same monoclonal antibody as instantly claimed in an amount of about 500-5000mg,1000-3000mg, 2000-5000mg, 3000-5000mg, 500…..5000mg per dose (claims 1 and 3-22). While the claims of the ‘910 Application do not recite the dose range that is exactly identical to the claimed range of 10-60mg/kg,10-40mg/kg, about 20-60mg/kg, about 40-60mg/kg, about 10, 15, 25, 30, 35, 40, 45, 50,55, 60mg/kg or any value in between per dose as recited in instant claims, Mercken, Griswold-Prenner and Adolfsson teach these dose ranges for the reasons set forth above under the 103 rejection. The provisional rejection is maintained of until a terminal disclaimer is filed.
Conclusion
7. NO CLAIM IS ALLOWED.
8. Any inquiry concerning this communication or earlier communications from the examiner should be directed to CHANG-YU WANG whose telephone number is (571)272-4521. The examiner can normally be reached on Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
January 10, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675