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
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
This action is in response to the papers filed on June 11, 2026. Pursuant to amendment filed June 11, 2026, claims 1 and 3 have been amended. Claims 30 is newly added.
Election/Restrictions
In response to the restriction requirement filed March 07, 2024, Applicants’ election with traverse of Group I, drawn to a product of patient-derived amyloid xenograft (PDAX) non-human animal model, wherein the animal is characterized by an implant of amyloid fibrils derived from the tissue or organ of a patient suffering from an amyloidosis or amyloid-related disease, wherein the amyloid and amyloid fibrils, was previously acknowledged. Applications species election of implantation site being skin was additionally previously acknowledged.
Claims 4-16 and 18-23 were previously withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. The requirement for restriction between Groups I, II, and VI is maintained for reasons of record and was made FINAL. Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution.
Therefore, claims 1, 3, and 24-30 are currently under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of the International Application No. PCT/EP2019/080829, filed November 11, 2019. The instant application claims foreign priority under 35 U.S.C. 119(a)-(d) to European Patent Application EP18205502.0, filed on November 09, 2018. A certified copy of the foreign patent application has been provided with the instant application.
Thus, the earliest possible priority for the instant application is November 09, 2018.
Withdrawn- Claim objections
In view of Applicants' amendment to claims 1 and 3, correcting the minor informalities, the objections to improper form are moot and have been withdrawn.
Maintained & Modified Claim Rejections - 35 USC § 103
Claims 1, 3, and 24-29 remain rejected, and claim 30 is newly rejected under 35 U.S.C. 103 as being unpatentable over Liu et al (US 2016/0251418 A1), in view of Saelices et al. (Proc Natl Acad Sci USA. 2018 Jul 17;115(29):E6741-E6750.), Tennent (Methods Enzymol. 1999:309:26-47.), and Yoshimura et al. (Bioconjug Chem. 2016 Jun 15;27(6):1532-9. Epub 2016 May 24.). This is a modified rejection necessitated by Applicants’ amendments to the claims in the response filed on June 6, 2026.
Regarding claim 1, Liu teaches antibodies directed against aggregated transthyretin (TTR) and the use of non-human animal models, including mice, for evaluating therapeutic activity against TTR amyloidosis. Liu further teaches implantation models involving aggregated TTR, including subcutaneous implantation in mice, and identifies tissue including heart, nerve, kidneys, and other organs as relevant sites of ATTR deposition, along with fibril forms of TTR also referred to as ATTR ([0207-0209], [0268], [0296], [0312-0315], [0457]).
While Liu teaches a non-human animal model comprising aggregated TTR material implanted in an animal and used for evaluating activity of an anti-TTR therapeutic, Liu does not expressly teach that the implanted ATTR fibrils are obtained from a tissue or organ of a human patient suffering from amyloidosis. However, before the effective filing date, the ordinary artisan would have recognized the generation of a patient-derived amyloid xenograft in animal models was a routine, conventional, and established laboratory practice, further in view of Saelices, Tennent and Yoshimura.
Saelices teaches amyloid fibrils comprising ATTR that are obtained from human patients suffering from ATTR amyloidosis, specifically teaching extraction of ATTR fibrils from cardiac tissue of affected patients, including in vivo seeding (Abstract; pg. 6745, column 1, para. 2; pg. 6746, column 1-2 bridging para.). Tennent further teaches established methods for isolating amyloid fibrils from human amyloidotic tissues, including aqueous extraction techniques that yield fibrillar material suitable for biochemical, structural, and functional study (pg. 26, para. 2; pg. 27, para. 2; pg. 32, para. 3; pg. 33, Section: Standard Protocol for Isolation of ex Vivo Amyloid Fibrils). Yoshimura additionally teaches an in vivo amyloid model in which amyloid aggregates are implanted into mice to form localized deposits that can be used for in vivo study (Abstract; pg. 1536, column 1, para. 2).
Thus, before the effective filing date, the ordinary artisan would have found it obvious to use patient-derived ATTR amyloid fibrils, as taught by Saelices, obtainable as taught by Tennent, as the amyloid material in an implantation in vivo model, as taught by Liu and exemplified by Yoshimura. The ordinary artisan would have been motivated to apply this known technique to provide an implanted amyloid substrate that more faithfully recapitulates the pathological ATTR material present in human disease while retaining the advantages of a localized, experimentally controllable in vivo model for evaluating amyloid-targeting therapeutics. Liu explicitly recognizes the utility of in vivo models for testing agents directed against aggregated TTR, while Saelices teaches that ATTR amyloid material may be obtained directly from affected human tissue. The person of ordinary skill in the art would had a reasonable expectation of success in producing such model since Tennent establishes that amyloid fibrils can be isolated from human amyloidotic tissue in a form suitable for further study, Saelices establishes that patient-derived ATTR amyloid material remains experimentally usable after isolation, and Liu and Yoshimura establish that amyloid or amyloidogenic aggregated material may be implanted and maintained in non-human animals for in vivo investigation.
Regarding claim 3, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 1 obvious. Furthermore, Yoshimura explicitly teaches that amyloid models can be generated in mice by implantation of amyloid aggregates into animals, without reliance on expression of a transgene in the host animal (pg. 1527, column 1). Moreover, where the exogenous patient-derived ATTR fibrils themselves provide the implanted amyloid substrate, endogenous transgenic production of human TTR in the host animal would not have been necessary to establish the localized implant.
Regarding claim 24, and independent product-by-process claim, the teachings of Liu, Saelices, Tennent, and Yoshimura are explained above. Again, Liu teaches antibodies targeting aggregated transthyretin (TTR) and the use of animal models, including mice, for evaluating therapeutic activity against ATTR amyloidosis ([0207-0209], [0268], [0296], [0312-0315], [0457]). In view of the teachings of Liu, the ordinary artisan would have recognized the utility of in vivo models comprising aggregated ATTR deposits in the prior art. However, Liu does not teach a model generated by implanting patient-derived amyloid fibrils into an animal.
Saelices teaches amyloid fibrils comprising ATTR obtained from human patients suffering from ATTR amyloidosis, including extraction from cardiac tissue (Abstract; pg. 6745, column 1, para. 2; pg. 6746, column 1-2 bridging para.). Tennent teaches a method for isolating amyloid fibrils from human amyloidotic tissue via aqueous extraction (pg. 33, Section: Standard Protocol for Isolation of ex Vivo Amyloid Fibrils). Yoshimura teaches an in vivo amyloid model in which amyloid aggregates are implanted into mice to form localized deposits for study (pg. 1537, column 1). Thus, the ordinary artisan would have found it obvious to combine the teachings by using patient-derived ATTR-fibrils, as taught by Saelices and Tennent, in an implantation-based model as taught by Yoshimura, motivated by Liu’s teachings and recognition of the utility physiologically relevant in vivo models for evaluating ATTR therapeutics ([0207-0209]; [0268]; [0312-0315]; 0457).
Regarding claim 25, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 24 obvious. Additionally, Liu teaches the association with transthyretin deposits and cardiac tissues ([0004]; [0027-0029]; [0177]; [0194]). Liu also teaches subcutaneous administration and mice skin implantation ([0296]). Furthermore, Saelices expressly teaches extraction of ATTR fibrils from cardiac tissue of human patients with ATTR amyloidosis (Abstract; pg. 6748, column 1, para. 7; pg. 6749, column 1, para. 5). The ordinary artisan would have found it obvious to use cardiac-derived ATTR fibrils in the combined model because cardiac involvement was well known, as taught by Liu and Saelices, and clinically significance to ATTR amyloidosis. The fibrils represent a relevant and readily available source of patient-derived amyloid material, and a person of ordinary skill in the art would have had a reasonable expectation of success in using such fibrils in an implantation model.
Regarding claim 26, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 1 obvious. Furthermore, Tennent teaches the isolation of amyloid fibrils from human tissue in a form suitable for structural and biochemical study (pg. 27, para. 2), and Saelices teaches the use of patient derived fibrils with functional properties and maintained native TTR structure (pg. 6742, column 1, para. 1-2). Saelices teaches patient-derived ATTR fibrils that retain fibrillar structure and functional seeding activity following isolation and sonication. Hence, the ordinary artisan would have recognized that fibrils isolated from tissue retain their disease-relevant conformation.
Regarding claim 27, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 1 obvious. Liu teaches both aggregated and non-native forms of TTR (Examples 13 and 14), and Saelices and Tennant teach amyloid fibrils derived from tissue, which are aggregated structures (Abstracts). The ordinary artisan would have recognized amyloid fibrils are implicitly high molecular weight aggregates of protein. Therefore, since the prior art teaches implantation of amyloid fibrils, the presence of high molecular weight aggregates would have been obvious to the ordinary artisan. Amyloid fibrils are themselves higher-order aggregated protein assemblies, and a person of ordinary skill in the art would have understood patient-derived amyloid fibrils to comprise high molecular weight protein aggregates due to their fibrillar amyloid structure.
Regarding claim 28, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 24 obvious. Additionally, Tennent teaches isolation of amyloid fibrils from human amyloidotic tissues by homogenization and aqueous extraction, which avoids the use of harsh denaturing conditions. Therefore, the ordinary artisan would have recognized the use of cold buffers and repeated homogenization steps to represent routine laboratory techniques for preserving protein structure and facilitating extraction (pg. 27, para. 2). Tennent teaches the utility of buffers containing EDTA, including the selection of Tris-EDTA as the buffer (pg. 30, para. 2).
Regarding claim 29, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 24 and 28 obvious. Additionally, Tennent teaches purification of amyloid fibrils from tissue to obtain relatively pure preparations suitable for analysis. The use of salt precipitation and centrifugation to purify and concentrate protein aggregates, including with NaCl and EDTA would have been obvious to the ordinary artisan, in view of the teachings of Tennent (pg. 43- 44 bridging para.; pg. 34, para. 2; pg. 35, para. 3; pg. 47, para. 2).
Regarding claim 30, the combined teachings of Liu, Saelices, Tennent, and Yoshimura render claim 1 obvious. Yoshimura teaches an amyloid implantation model that does not rely on expression of a transgene in the host animal. Additionally, Saelices and Tennent provide the patient-derived amyloid fibrils that serve as the exogenous amyloid substrate. The ordinary artisan would have found it obvious to employ a wild-type animal as the host because transgenic expression of the amyloid protein would not be required where the amyloid fibrils are supplied by implantation.
Response to Applicants' arguments as they apply to the rejection of claims 1, 3, and 24-29
Applicant’s arguments filed June 11, 2026, have been fully considered but they are
not persuasive.
At pages 6-9 of the remarks filed on June 11, 2026, Applicants essentially argue the following:
Applicant argues that the cited referenced do not teach the claimed patient-derived ATTR implantation model because Liu uses artificially generated TTR aggregates, Saelices and Tennent employ processing such as sonication, and Yoshimura concerns amylin rather than AATTR.
This argument is not persuasive because in response to applicant's arguments against the references individually, one 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). Liu provides the ATTR therapeutic model and implantation context. Saelices provides patient-derived ATTR amyloid material obtained from human tissue. Tennent provides methods for isolating amyloid fibrils from human amyloidotic tissue. Yoshimura further demonstrates and teaches the use of implanted amyloidogenic material in localized in vivo models.
Applicant argues the claimed patient-derived ATTR fibrils are structurally and functionally different from Liu’s aggregates because they retain native conformation, contain associated proteins such as apolipoprotein A1, and remain accessible to infiltrating immune cells rather than being shielded by Matrigel.
This argument is not persuasive because the claims do not require presence of apolipoprotein A1 or other associated proteins, exclusion of Matrigel or another carrier, immune-cell infiltration, or any specified fibril-clearance phenotype. In response to Applicant's argument that the references fail to show certain features of the invention, it is noted that the features upon which applicant relies (i.e., presence of apolipoprotein A1) are not recited in the rejected claim(s). Although the claims are interpreted in light of the specification, limitations from the specification are not read into the claims. See In re Van Geuns, 988 F.2d 1181, 26 USPQ2d 1057 (Fed. Cir. 1993).
Furthermore, Tennent teaches the isolation of amyloid fibrils from human tissue in a form suitable for structural and biochemical study (pg. 27, para. 2), and Saelices teaches the use of patient derived fibrils with functional properties and maintained native TTR structure (pg. 6742, column 1, para. 1-2).
Thus, Tennent teaches isolation of tissue-derived amyloid fibrils under conditions that preserve fibrillar structure and teaches isolation methods that preserve native fibril conformation. Saelices further teaches patient-derived ATTR fibrils that retain structural and functional amyloid properties following isolation. Hence, the ordinary artisan using patient-derived ATTR fibrils in the implantation model suggested by Liu and Yoshimura would have been motivated to preserve the native fibrillar confirmation during isolation and implantation because preservation of the disease related fibril structure would maintain the physiological relevance for which patient-derived fibrils were selected.
Applicant argues that there is no sufficient reason to combine the references and no reasonable expectation of success in forming the claimed model.
This argument is not persuasive because, 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).
In this case, Saelices teaches patient-derived ATTR amyloid material from affected human tissue, Tennent teaches isolation of amyloid fibrils from human amyloidotic tissue for further study, and Liu and Yoshimura establish implantation-based in vivo models using aggregated amyloidogenic material. Thus, the ordinary artisan would have reason to use patient-derived ATTR material in an implantation model to provide a more disease relevant amyloid substrate while retaining a localized and experimentally controllable system for evaluating amyloid-targeting therapeutics, with a reasonable expectation that the implanted material could be maintained and studied in vivo.
Applicant argues that the claimed model exhibits advantageous immune-cell infiltration, fibril phagocytosis, and accelerated fibril clearance following administration of an anti-TTR antibody.
This argument is not persuasive because these alleged advantages are not required by the claims, and applicant has not established that the asserted results are commensurate in scope with the rejected claims. Furthermore, this argument is not persuasive because the arguments of counsel cannot take the place of evidence in the record. In re Schulze, 346 F.2d 600, 602, 145 USPQ 716, 718 (CCPA 1965). Examples of attorney statements which are not evidence, and which must be supported by an appropriate affidavit or declaration include statements regarding unexpected results, commercial success, solution of a long-felt need, inoperability of the prior art, invention before the date of the reference, and allegations that the author(s) of the prior art derived the disclosed subject matter from the inventor or at least one joint inventor.
Conclusion
Claims 1, 3, and 24-30 are rejected. No claims are 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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to JOEL D LEVIN whose telephone number is (571)270-0616. The examiner be reached 8:00 am to 5:00 pm, Monday through Friday.
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/J.D.L./Examiner, Art Unit 1633
/FEREYDOUN G SAJJADI/Supervisory Patent Examiner, Art Unit 1699
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