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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 July 1, 2025 has been entered.
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 July 01, 2025. Pursuant to amendment filed July 01, 2025, claims 4-12, 15-16, 18-22 are withdrawn. Claims 2, 13-14, and 17 are canceled. Claims 24-25 are currently amended. Claims 26-29 are 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Claims 4-16 and 18-23 were previously withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking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 Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution.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 24-29 are currently examined on the merits to which the following grounds of rejection are applicable.
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.
Information Disclosure Statement
The information disclosure statements (IDS) submitted on July 1, 2025 and August 14, 2025 are presently acknowledged. The submission in compliance with the provisions of 37 CPR 1.97. Accordingly, the information disclosure statements are being considered by the examiner.
Claim Objections
Claim 1 should recite “A patient-derived amyloid xenograft (PDAX) non-human animal model, wherein the patient-derived amyloid xenograft (PDAX) non-human animal model
is a mouse, a rat, or a non-human primate, wherein the patient-derived amyloid xenograft (PDAX) non-human animal model comprises amyloid fibrils obtained from a tissue or organ of a patient suffering from an amyloidosis or amyloid-related disease, wherein the amyloid fibrils are subcutaneously or subcapsularly implanted in a tissue of the patient-derived amyloid xenograft (PDAX) non-human animal model selected from the group consisting of skin, a kidney, peritoneum, muscle, brain, a ventricle, a nerve, an eye, a tongue, and heart, and
wherein the amyloid fibrils comprise amyloid transthyretin (ATTR).
Claim 2 should recite “wherein the patient-derived amyloid xenograft (PDAX) non-human animal model is non-transgenic”.
Withdrawn- Claim Rejections - 35 USC § 103
In view of Applicants amendment to the instant claims, the rejection under 35 U.S.C. 103 to claims 1, 3, and 24-25 as being unpatentable over Slamova (Slamova, Thesis: "Modelling amyloidosis in mice," Doctor of Philosophy, Centre for Amyloidosis and Acute Phase Proteins, Division of Medicine, University College London, 2016 (294 pages), in view of Mambule et al. "Enhancement of AA-amyloid formation in mice by transthyretin amyloid fragments and polyethylene glycol," Biochim. Biophys. Acta. 1474(3):331-336 (2000), and further in view of Wall et al. (PLoS One. 2012;7(12):e52686. Epub 2012 Dec 26.) has been withdrawn. Applicants’ arguments are moot in view of the withdrawn rejection. A response to Applicant’s arguments pertinent to a new or remaining rejection can be found below.
New Claim Rejections - 35 USC § 103
Claims 1, 3, and 24-29 are 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.), Yoshimura et al. (Bioconjug Chem. 2016 Jun 15;27(6):1532-9. Epub 2016 May 24.).
Regarding claim 1, Liu teaches anti-transthyretin antibodies for ATTR and identifies the animal models for testing activity against a TTR amyloidosis, including subcutaneous skin implantation models. Liu also teaches the use of animal models, including mice for evaluating therapeutic activity against ATTR amyloidosis and that ATTR amyloid deposits occur in tissues such as the heart, nerves, kidneys, and other organs, along with fibril forms of TTR also referred to as ATTR ([0207-0209], [0268], [0296], [0312-0315], [0457]). However Liu does not explicitly teach a model in which amyloid fibrils obtained from a patient are directly implanted into an animal.
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 methods for isolating amyloid fibrils from human amyloidotic tissues, including homogenization and aqueous extraction techniques that yield fibrillar material suitable for biochemical and structural 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 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 fibrils, as taught by Saelices and Tennent, in an implantation-based model as taught by Yoshimura, in order to improve physiological relevance and provide a controllable in vivo system for evaluating amyloid-targeting therapeutics as motivated and explicitly, motivated by the teachings of Liu on in vivo modeling. In doing so, the ordinary artisan would have had a reasonable expectation of success at generating the ATTR fibril implantation model using amyloid fibrils obtained from a tissue or organ of a patient suffering from an amyloidosis or amyloid-related disease.
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).
Regarding claim 24, and independent product-by-process claim, the teachings of Liu, Saelices, Tennent, and Yoshimura are explicated 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 method for isolating amyloid fibrils from human amyloidotic tissue via homogenization and 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 is 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 of native TTR structure (pg. 6742, column 1, para. 1). 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 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). Additionally, 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.
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).
Response to Applicants’ amendment as they apply to rejection of claims 1, 3, and 24-25 under 35 USC § 103
Applicant’s arguments with respect to claims 1, 3, and 24-25 have been considered but are moot because the new ground of rejection does not rely on any reference applied in the prior rejection of record for any teaching or matter specifically challenged in the argument.
Conclusion
Claims 1, 3, and 24-29 are rejected. No claims are allowed.
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 can normally be reached Fulltime Teleworker.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Christopher Babic can be reached at (571) 272-8507. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/J.D.L./Examiner, Art Unit 1633
/CHRISTOPHER M BABIC/Supervisory Patent Examiner, Art Unit 1633