Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 20, 2026 has been entered.
RESPONSE TO AMENDMENT
Status of Application/Amendments/claims
3. Applicant’s amendment filed January 20, 2026 is acknowledged. Claims 1-23 are cancelled. Claim 32 is amended. Claims 24-32 are pending in this application. Election was treated as without traverse in the reply filed on September 12, 2024.
4. Claims 24-32 are under examination in this office action.
5. Applicant’s arguments filed on January 20, 2026 have been fully considered but they are not deemed to be persuasive for the reasons set forth below.
Claim Rejections/Objections Withdrawn
6. The objection to claim 32 is withdrawn in response to Applicant’s amendment to the claim.
Claim Rejections/Objections Maintained
In view of the amendment filed on January 20, 2026, the following rejections are maintained.
Claim Rejections - 35 USC § 103
7. The following is a quotation of pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived 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 pre-AIA 35 U.S.C. 103(a) 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 under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102€, (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 24-32 stand rejected under pre-AIA 35 U.S.C. 103(a) as obvious over Delacourte et al. (US2005/0175626) in view of Gellerfors et al. (WO2005/123775). The rejection is maintained for the reasons of record and the reasons set forth below.
Claims 24-32 as amended are drawn to a method of producing an antibody which binds to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers but exhibits no or substantially no binding with full length Ab monomers, the method comprising i) administering an antigen comprising soluble, stabilized N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers to a non-human animal; ii) collecting antibodies formed against the antigen. Dependent claims are directed to further screening for antibodies that i) bind to at least one N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomer and ii) exhibit substantially no binding to full length Ab monomers including Ab1-42 monomers; and isolating the antibodies (claims 25 and 27), screening for antibodies that bind to wild-type human N-terminal truncated Ab protofibrils; and isolating the antibodies (claim 26), wherein the antigen comprises one or more Abx-y, wherein x is 3(pE) or 11(pE) and y is 38, 39, 40, 41, 42 or 43, in any combination, including Ab3(pE)-42 and/or Ab11(pE)-42 (claims 29-31), wherein the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomer is stabilized with a hydrophobic organic agent (claim 32).
Response to Arguments
On p. 4-7 of the response, Applicant acknowledges that i) Delacourte teaches a method for preparation of an antibody comprising immunizing an animal with a N-terminal truncated and/or posttranslational modified Ab peptide (i.e. Monomer) and the use of short peptides of 8 amino acids for generation of antibodies (see p.76, claim 50; p. 5, para. [0060]; p. 19, para.[0201], and p. 28, table 4); ii) Gellerfors teaches protofibrils of Ab42 without N-terminal pyroglutamate modification, N-terminal truncated Ab without N-terminal pyroglutamate modification or Ab mutants. But Applicant argues that: i) Gellerfors does not disclose the use of stabilized N-terminal truncated N-terminal pyroglutamate-modified Ab protofibrils/oligomers for producing an antibody and nothing in combination of Delacourte and Gellerfors would have led to the claimed method of claim 24; ii) there was no motivation to modify the teaching of the cited arts because Delacourte uses short Ab peptides conjugated to KLH to achieve immunogenicity whereas Gellerfors is directed to antigen stabilization to prevent aggregation of Ab protofibril to fibril. Applicant cites In re Gordon, In re Fine in support of the arguments.
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. Applicant cannot show nonobviousness by attacking references individually where the rejections are based on combinations of references. See In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981); In re Merck & Co., 800 F.2d 1091, 231 USPQ 375 (Fed. Cir. 1986).
The reference of Gellerfors is cited to support the limitation “the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers are stabilized with a hydrophobic organic agent” recited in claims 24 and 32 and the motivation and an expectation of success in using the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers that are stabilized with a hydrophobic organic agent in the Delacorute’s method because Gellerfors teaches the benefits of generating antibodies from soluble stabilized N-terminal truncated protofibril/oligomers that are stabilized with a hydrophobic organic agent. Gellerfors teach that antibodies raised against soluble stabilized N-terminal truncated protofibril/oligomers that are stabilized with a hydrophobic organic agent can bind naturally occurring amyloid plaques in the brain comprising different species of N-terminal truncated protofibril/oligomers (p.16, 2nd paragraph; p. 18-19, Examples 2-3).
ii. In response to applicant’s argument that there is no teaching, suggestion, or motivation to combine the references, the examiner recognizes that obviousness may be established by combining or modifying the teachings of the prior art to produce the claimed invention where there is some teaching, suggestion, or motivation to do so found either in the references themselves or in the knowledge generally available to one of ordinary skill in the art. See In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988), In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992), and KSR International Co. v. Teleflex, Inc., 550 U.S. 398, 82 USPQ2d 1385 (2007).
Specific statements in the references themselves which would spell out the claimed invention are not necessary to show obviousness, since questions of obviousness involve not only what references expressly teach, but what they would collectively suggest to one of ordinary skill in the art. See CTS Corp. v. Electro Materials Corp. of America 202 USPQ 22 (DC SNY 1979); and In re Burckel 201 USPQ 67 (CCPA 1979).
It is not necessary that the claimed invention be expressly suggested in any one or all of the references to justify combining their teachings; rather the test is what the combined teachings of the references would have suggested to those of ordinary skill in the art. In re Keller, 642 F.2d 413, 208 USPQ 871 (CCPA 1981). Only a reason, suggestion or motivation need appear in the cited prior art in order to combine references under 35 U.S.C. 103. Pro Mold Tool Col. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573, 37 USPQ2d 1626, 1629 (Fed. Cir. 1996).
In this case, Delacourte (US2005/0175626) teaches a method of producing an antibody binding to N-terminal truncated Ab variant peptides including N-terminal truncated, N-terminal pyroglutamate-modified Ab, comprising administering to a non-human animal the N-terminal truncated, N-terminal pyroglutamate-modified Ab variant peptides and collecting antibodies formed against the N-terminal truncated, N-terminal pyroglutamate-modified Ab variant peptides, wherein the N-terminal truncated, N-terminal pyroglutamate-modified Ab variant peptides include pyroglutamylation at position 3 of an N-terminal truncated Abx-y (which is 3(pE)), wherein x is 3(pE), 4(pE)….10(pE), and y is 42 or in any combination as recited in instant claims (see paragraphs [0025]-[0035]; [0068]-[0069]; [0014]; [0017]-[0018]; [0195]; p25, table 1 (Ab3(pE)-42, Ab3(pE)-40); [0083]-[0091]; p.76, claims 50-54; [0200]-[0203], Example 2; [0083]-[0093]; [0095]-[0096];[0102]). Delacourte teaches that the antigen comprises at least 50% N-terminal truncated, N-terminal pyroglutamate-modified Ab variant peptides including one or more of Ab3(pE)-42, Ab4(pE)-42… or Ab10(pE)-42 in any combination as in claims 28-31 (see paragraphs [0067]-[0069]; [0071]; [0096]; [0102]; p.76, claims 50-54). Delacourte also teaches further screening for antibodies that bind to at least one N-terminal truncated, N-terminal pyroglutamate-modified Ab variant peptides and exhibit no or substantially no binding to full length Ab monomers including Ab1-42 monomers or bind to wild-type human N-terminal truncated Ab protofibrils; and isolating the antibodies as in claims 25-27 (see paragraphs [0083]-[0093]; [0096]; [0102]; p.76, claims 50-54).
While Delacourte does not explicitly teach that the N-terminal truncated, N-terminal pyroglutamate-modified Ab variants are stabilized as protofibril/oligomers as in claim 24, or stabilized by a hydrophobic organic agent as in claim 32, Gellerfors teaches the benefits of generating antibodies from soluble stabilized N-terminal truncated protofibril/oligomers that are stabilized with a hydrophobic organic agent.
Gellerfors teach that antibodies raised against soluble stabilized N-terminal truncated protofibril/oligomers that are stabilized with a hydrophobic organic agent can bind naturally occurring amyloid plaques in the brain comprising different species of N-terminal truncated protofibril/oligomers (p.16, 2nd paragraph; p. 18-19, Examples 2-3).
The teaching of Gellerfors provides motivation and an expectation of success in using soluble, stabilized N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers that are stabilized by a hydrophobic organic agent in the Delacourte’s method to generate antibodies can bind naturally occurring amyloid plaques in the brain comprising different species of N-terminal truncated protofibril/oligomers or bind to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers but exhibits no or substantially no binding with full length Ab monomers.
A person of ordinary skill in the art would have recognized that selecting and applying the known benefits of generation of antibodies from soluble stabilized N-terminal truncated protofibril/oligomers that are stabilized with a hydrophobic organic agent and the known technique of stabilizing the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers by a hydrophobic organic agent disclosed by Gellerfors to the Delacourte’s method would have yielded the predictable result of producing an antibody that can bind naturally occurring amyloid plaques in the brain comprising different species of N-terminal truncated protofibril/oligomers or bind to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers but exhibits no or substantially no binding with full length Ab monomers as instantly claimed, and resulted in an improved method.
Using the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers stabilized by a hydrophobic organic agent in the Delacourte’s method would generate antibodies binding to different species of N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42 and with no, substantially no binding with full length Ab monomers, and would expand application of the Delacourte’s method and obtain an antibody that binds naturally occurring amyloid plaques in the brain comprising different species of N-terminal truncated protofibril/oligomers or bind to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers but exhibits no or substantially no binding with full length Ab monomers, and would increase patient’s satisfaction with diagnosis or treatment of Alzheimer’s disease or amyloid related diseases using antibodies specifically binding to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42.
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 technique of stabilizing the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers by a hydrophobic organic agent to the Delacourte’s method, and yield the predictable result of producing an antibody which binds to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers including Ab3(pE)-42 but exhibits no or substantially no binding with full length Ab monomers.
Accordingly, the rejection of claims 24-32 under pre-AIA 35 U.S.C. 103(a) as obvious over Delacourte in view of Gellerfors is maintained.
Claim Rejections - 35 USC § 103
8. Claims 29-30 stand rejected under pre-AIA 35 U.S.C. 103(a) as obvious over Delacourte et al. (US2005/0175626) in view of Gellerfors et al. (WO2005/123775) as applied claims 24-32 above, and further in view of Russo et al. (FEBS Lett. 1997;409:411-416) and Tekirian et al. (J. Alzheimer’s Disease 2001; 3:241-248). The rejection is maintained for the reasons of record and the reasons set forth below.
Response to Arguments
On p. 7 of the response, Applicant argues that for the reasons set forth above independent claim 24 is non-obvious over 35USC §103. Thus, claims 29-30 are also non-obvious over Delacourte in view of Gellerfors, Russo and Tekirian.
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. For the reasons set forth above, Delacourte and Gellerfor do teach the method recited in claims 24-32.
ii. While Delacourte and Gellerfors do not explicitly teach that the antigen comprises Ab11(pE)-42, Russo and Tekirian teach this limitation and provide motivation and an expectation of success in using an antigen comprising Ab11(pE)-42 in the method of Delacourte and Gellerfor to generate antibodies against the antigen comprising Ab11(pE)-42 or in combination with Ab3(pE)-42 because Russo teaches that soluble Ab isolated from plaques in the brain of AD patients consists of the full-length Ab1-42, and N-terminal truncated, N-terminal pyroglutamate-modified Ab including Ab3(pE)-42 and Ab11(pE)-42, and both pyroglutamate-modified Ab: Ab3(pE)-42 and Ab11(pE)-42 and the full length Ab form a stable aggregate that is water soluble (see abstract) and also teach antibodies against anti-N3(pE) and anti-N11(pE) Ab (see p. 411, 2nd col., section: antibodies); and Tekirian teach several forms of N-terminal truncated, N-terminal pyroglutamate-modified Ab isoforms including Ab3(pE)-x and Ab11(pE)-x, wherein x is 40 and 42 are critical contributors in the course of Alzheimer’s disease (see p. 242, 2nd col. section pyroglutamated Ab (AbN(pE)-x) to p. 244).
A person of ordinary skill in the art would have recognized that selecting and applying the known Ab3(pE)-42 and Ab11(pE)-42 included in an antigen comprising N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers disclosed by Russo and Tekirian to the method of Delacourte and Gellerfors would have yielded the predictable result of producing an antibody which binds to N-terminal truncated, N-terminal pyroglutamate-modified Ab Ab protofibrils/oligomers including Ab3(pE)-42 and Ab11(pE)-42 but exhibits no or substantially no binding with full length Ab monomers, and resulted in an improved method.
Using and including the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42 and Ab11(pE)-42 as an antigen in the method of Delacourte and Gellerfors would generate antibodies binding to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42 and Ab11(pE)-42 and with no or substantially no binding with full length Ab monomers, and would expand application of the method of Delacourte and Gellerfors and would increase patient’s satisfaction with diagnosis or treatment of Alzheimer’s disease or amyloid related diseases using antibodies specifically binding to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42 and Ab11(pE)-42.
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 antigen comprising the N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibril/oligomers including Ab3(pE)-42 and Ab11(pE)-42 disclosed by Russo and Tekirian that are stabilized with a hydrophobic organic agent to the method of Delacourte and Gellerfors, and yield the predictable result of producing an antibody which binds to N-terminal truncated, N-terminal pyroglutamate-modified Ab protofibrils/oligomers including Ab3(pE)-42 and Ab11(pE)-42 but exhibits no or substantially no binding with full length Ab monomers.
Accordingly, the rejection of claims 29-30 under pre-AIA 35 U.S.C. 103(a) as obvious over Delacourte in view of Gellerfors, Russo and Tekirian is maintained.
Conclusion
9. NO CLAIM IS ALLOWED.
10. 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 Monday-Thursday, 7:00am-5:00pm EST.
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Chang-Yu Wang
April 17, 2026
/CHANG-YU WANG/Primary Examiner, Art Unit 1675
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