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
Request for Continued Examination Under 37 CFR 1.1143
A request for continued examination (RCE) 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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 mailed on July 25, 2025 has been entered.
New claims 38-41 are acknowledged.
Claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-41 are pending in the instant application.
Accordingly, claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-41 have been examined on the merits as detailed below:
Response to Arguments
Applicant's Amendment and Response filed July 25, 2025 has been considered. Communications, rejections and/or objections not reiterated from the previous Office Action mailed October 28, 2024 are hereby withdrawn. Any arguments addressing said rejections and/or objections are moot. The following rejections and/or objections are either newly applied or are reiterated and are the only rejections and/or objections presently applied to the instant application.
Priority
As an initial matter, new claims 38-41 have been added with Applicant’s RCE filed July 25, 2025.
The present application is a continuation of 16468953, filed 06/12/2019, now abandoned. 16468953 is a National Stage entry of PCT/US17/66331, International Filing Date: 12/14/2017. PCT/US17/66331 claims priority from Provisional Application 62435127, filed 12/16/2016.
Provisional Application 62435127 does not provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application. It does not appear that any of the newly filed claims are supported in the Provisional Application.
For this reason, newly filed claims 38-41 have been afforded priority to the filing date of PCT/US17/66331, International Filing Date: 12/14/2017. If Applicants believe claims 38-41 deserves priority to an earlier filing date, the Examiner urges Applicant to point to, with particularity, where support can be found for the claims as filed in any early application for which Applicants claim priority to.
Double Patenting
In the previous Office Action mailed October 28, 2024, claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-37 were rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 42-75 of U.S. Patent No. 10,208,307 (hereinafter, “’307 Patent”) in view of Vinik et al. (Journal of the Peripheral Nervous System, Vol. 19, ABSTRACT).
In the previous Office Action mailed October 28, 2024, claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-37 were rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 10,683,501 (hereinafter, “’501 Patent”) in view of Vinik et al. (Journal of the Peripheral Nervous System, Vol. 19, ABSTRACT).
In the previous Office Action mailed October 28, 2024, claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-37 were rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 1-28 of U.S. Patent No. 11,286,486 (hereinafter, “’486 Patent”) in view of Vinik et al. (Journal of the Peripheral Nervous System, Vol. 19, ABSTRACT).
In the previous Office Action mailed October 28, 2024, claims 2, 7-13, 16-18, 21, 22, 24-26, 28, 30, 32, 33 and 35-37 were rejected on the grounds of nonstatutory obviousness-type double patenting as being unpatentable over claims 34-44 of U.S. Patent No. 12,049,628 (hereinafter, “’628 Patent”) in view of Vinik et al. (Journal of the Peripheral Nervous System, Vol. 19, ABSTRACT).
These rejections are maintained for the reasons of record set forth in the previous Office Action mailed October 28, 2024.
NOTE: New claims 38-41 are drawn to subject matter within the scope of the rejected claims and, if present, would have been rejected in the prior Office Action. Therefore, the instant rejections apply to new claims 38-41 as well.
Response to Arguments
As an initial matter, in response to these rejections, Applicants traverse with arguments against the '307 Patent; the '501 Patent; and the '486 Patent – but there are not arguments in reference to the rejection against the ‘628 Patent in view of Vinik et al. The rejection against the ‘628 Patent in view of Vinik et al. is therefore maintained.
Applicants traverse the ODP rejections against the '307 Patent; the '501 Patent; and the '486 Patent with arguments similar to those made in Applicant’s Arguments/Remarks filed October 16, 2024. In response, the Examiner will only address the new arguments and evidence made in Applicant’s traversal filed July 25, 2025.
Applicant’s first new argument disagrees that a person of ordinary skill in the art would have found at least each member of the fixed and weight-based doses disclosed in '307 Patent; the '501 Patent; and the '486 Patent obvious. Applicant submits that based on the significant teachings of weight-based dose regimens in the '307 Patent, the '501 Patent and the '486 Patent, and all the weight-based working Examples provided in the three Patents, it would not have been obvious to one of ordinary skill in the art to, first, select a totally different dosing regimen, i.e., a fixed dose regimen, and second, to select the specific fixed dose (i.e., about 25 mg to about 50 mg) required by the claims with a reasonable expectation of success.
This argument has been fully considered by the Examiner, but is not found persuasive because the '307 Patent, the '501 Patent and the '486 Patent are explicit in at least disclosing:
“The present invention provides methods of increasing a 6-minute walk test (6MWT) in a subject having a transthyretin (TTR)-associated disorder. The methods include administering to the subject a fixed dose of about 10 mg to about 600 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, or about 80 mg to about 500 mg, about 25 mg to about 300 mg, about 50 mg to about 300 mg, or about 80 mg to about 300 mg (e.g., about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 110, about 120, about 125, about 130, about 140, about 150, about 160, about 170, about 175, about 180, about 190, about 200, about 210, about 220, about 225, about 230, about 240, about 250 mg, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 325, about 330, about 340, about 350, about 360, about 370, about 375, about 380, about 390, about 400, about 410, about 420, about 425, about 430, about 440, about 450 mg, about 460, about 470, about 475, about 480, about 490, about 500, about 510, about 520, about 525, about 530, about 540, about 550, about 560, about 570, about 575, about 580, about 590, or about 600 mg) of a double stranded RNAi agent, wherein the double stranded RNAi agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to SEQ ID NO:2 (5′-UGGGAUUUCAUGUAACCAAGA-3′), wherein each strand is about 14 to about 30 nucleotides in length, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand comprises no more than 8 2′-fluoro modifications; wherein the antisense strand comprises no more than 6 2′-fluoro modifications; wherein the sense strand and the antisense strand each independently comprise two phosphorothioate linkages at the 5′-terminus; and wherein the sense strand is conjugated to at least one ligand.”
Given this disclosure the Examiner maintains it would have been obvious to one of ordinary skill in the art to select any one of the different dosing regimens disclosed. Also, given the weight-based working Examples provided in the '307 Patent, the '501 Patent and the '486 Patent, the Examiner maintains that selection of any one of the different dosing regimens, including the fixed dose of about 25 mg to about 50 mg, would reasonably expect to offer the same benefit as the weight-based dose reported in the working Examples.
Applicant’s second new argument is on the grounds that all the working Examples of the '307 Patent, the '501 Patent and the '486 Patent teach the use of weight-based doses to suppress TTR expression in vivo. Applicants submit that none of the Examples in the '307 Patent, the '501 Patent and the '486 Patent teach or suggest the administration of a fixed dose of a dsRNAi agent, let alone the specific fixed dose regimen (i.e., a fixed dose of about 25 mg to about 50 mg). Applicants argue that it is unclear why one of ordinary skill in the art would even be motivated to select a totally different dosing regimen, i.e., a fixed dose, as claimed, when the cited art teaches the success of a weight-based dosing regimen, let alone the specific fixed dose as claimed.
This argument is similar to Applicant’s first argument above and for the reasons previously discussed is not found to be persuasive.
Furthermore, each of the '307 Patent, the '501 Patent and the '486 Patent explicitly disclose:
“Those skilled in the art will recognize, or be able to ascertain using no more than routine experimentation, many equivalents to the specific embodiments and methods described herein”.
The Examiner maintains that using nothing more than routine experimentation, a person of ordinary skill in the art would have been motivated to select each member of the fixed and weight-based doses disclosed in '307 Patent; the '501 Patent; and the '486 Patent for the purpose of suppressing TTR expression in vivo. The fixed and weight-based doses are obvious choices made during the course of routine optimization and experimentation. Further, as discussed above, the ’307 Patent, and the ‘501 Patent and the ‘486 Patent, each explicitly teach and suggest a fixed dose of about 25 mg to about 50 mg. It is the Examiner's position that during the course of routine experimentation and optimization, a person of ordinary skill in the art would choose this specific dosing regimen. See MPEP 2144.05. Also, Applicant is reminded where the general conditions of a claim are disclosed in the prior art, discovering the optimum or workable ranges involves only routine skill in the art. See In re Aller, 105 USPQ 233.
Furthermore, KSR forecloses an obvious to try rationale is proper when the possible options for solving a problem are known, finite, and predictable, with a reasonable expectation of success. KSR, 550 U.S. at 418, 82 USPQ2d at 1396. See also MPEP § 2143(E). In the present case, the possible options of fixed and weight-based doses are known and finite. Further, as discussed above, a person of ordinary skill in the art would have found each member of the fixed and weight-based doses disclosed in '307 Patent; the '501 Patent; and the '486 Patent obvious and would reasonably expect the fixed doses offer the same benefit and treatment as the weight-based doses reported in the working Examples.
Applicants lastly argue that there is evidence of unexpected results; commercial success; and recognition by others which further demonstrates the non-obviousness of the claimed invention. Applicants rely on the § 1.132 Declaration by Dr. Gabriel Robbie (hereinafter, “The Robbie Declaration”) filed July 25, 2025.
The Examiner has considered the Robbie Declaration in full, however it is not found to be persuasive. As noted above, the '307 Patent, the '501 Patent and the '486 Patent are explicit in disclosing:
“The present invention provides methods of increasing a 6-minute walk test (6MWT) in a subject having a transthyretin (TTR)-associated disorder. The methods include administering to the subject a fixed dose of about 10 mg to about 600 mg, about 25 mg to about 500 mg, about 50 mg to about 500 mg, or about 80 mg to about 500 mg, about 25 mg to about 300 mg, about 50 mg to about 300 mg, or about 80 mg to about 300 mg (e.g., about 10, about 20, about 30, about 40, about 50, about 60, about 70, about 75, about 80, about 90, about 100, about 110, about 120, about 125, about 130, about 140, about 150, about 160, about 170, about 175, about 180, about 190, about 200, about 210, about 220, about 225, about 230, about 240, about 250 mg, about 260, about 270, about 275, about 280, about 290, about 300, about 310, about 320, about 325, about 330, about 340, about 350, about 360, about 370, about 375, about 380, about 390, about 400, about 410, about 420, about 425, about 430, about 440, about 450 mg, about 460, about 470, about 475, about 480, about 490, about 500, about 510, about 520, about 525, about 530, about 540, about 550, about 560, about 570, about 575, about 580, about 590, or about 600 mg) of a double stranded RNAi agent, wherein the double stranded RNAi agent comprises a sense strand complementary to an antisense strand, wherein the antisense strand comprises a region complementary to SEQ ID NO:2 (5′-UGGGAUUUCAUGUAACCAAGA-3′), wherein each strand is about 14 to about 30 nucleotides in length, wherein substantially all of the nucleotides of the sense strand and substantially all of the nucleotides of the antisense strand are modified nucleotides, wherein the sense strand comprises no more than 8 2′-fluoro modifications; wherein the antisense strand comprises no more than 6 2′-fluoro modifications; wherein the sense strand and the antisense strand each independently comprise two phosphorothioate linkages at the 5′-terminus; and wherein the sense strand is conjugated to at least one ligand.”
Given this explicit disclosure, there is nothing unexpected or surprising about a fixed dosing regimen of about 25 mg to about 50 mg dsRNAi agent of the invention improving an indicia of quality of life being a 6-minute walk test (6MWT). See the Robbie Declaration, Figure 3. The '307 Patent, the '501 Patent and the '486 Patent are explicit that a person of ordinary skill in the art should reasonably expect such improvement from the methods of their invention.
Further, given the overall teachings of the '307 Patent, the '501 Patent and the '486 Patent, there is nothing unexpected about a fixed dosing regimen of about 25 mg to about 50 mg dsRNAi agent of the invention reducing TTR levels in patients, regardless of body weight. See Robbie Declaration, Figure 1. Each of the three Patents teach and suggest as much throughout their Disclosures/Specifications.
Regarding the improvement in quality of life as determined by Norfolk Quality of Life-Diabetic Neuropathy following administration of a fixed dosing regimen of about 25 mg to about 50 mg dsRNAi agent of the invention as reported in Figure 2 of the Robbie Declaration, a person of ordinary skill in the art would not find the evidence in the Declaration neither surprising nor unexpected. Based on the teachings and suggestions in the '307 Patent, the '501 Patent and the '486 Patent, in view of Vinik et al., the Examiner maintains that a person of ordinary skill in the art would reasonably expect such improvement.
The Examiner appreciates the data provided in the Robbie Declaration at Figures 1-5. However, the issue is that based on the explicit disclosures and teachings and suggestions provided in the ‘307 Patent, the ‘501 Patent and the ‘486 Patent, the experimental data with the fixed doses reported in the Robbie Declaration is obvious and would have been expected by the skilled artisan.
Concerning the secondary considerations of commercial success and recognition by others discussed in the Robbie Declaration, given the explicit disclosures and teachings and suggestions found in the ‘307 Patent, the ‘501 Patent and the ‘486 Patent, in view of Vinik et al., the evidence in the Declaration is not sufficient to overcome the nonstatutory double patenting rejections of record.
Regarding new claim 38, the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent do not necessarily teach that the methods of their inventions improves cardiac structure and function. However, the four Patents are directed to methods of treating amyloidosis. It is known in the art that amyloidosis often involves the heart, a condition known as cardiac amyloidosis or "stiff heart syndrome," where abnormal amyloid protein deposits buildup in the heart muscle. This buildup makes the heart walls stiff and thick, leading to heart failure, arrhythmias, and difficulty filling with blood. A person of ordinary skill in the art would reasonably expect the methods of treating amyloidosis as taught by the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent to improve cardiac function, absent some evidence to the contrary.
Regarding new claims 39 and 40, the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent do not necessarily teach the methods of their inventions reduce the expression level of a cardiac stress marker. However, the four Patents are directed to methods of treating amyloidosis. The prior art teaches treatment of amyloidosis reduces the expression level of the cardiac stress marker, N-terminal pro b-type natriuretic peptide (NT-proBNP). See the evidence of Merlini et al. (Leukemia (2 August 2016), Vol. 30, pages 1-8). Therefore, a person of ordinary skill in the art would reasonably expect the methods of treating amyloidosis as taught by the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent to reduce the expression level of NT-proBNP, absent evidence to the contrary.
Regarding new claim 41, the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent do not necessarily teach the methods of their inventions reduce the mean left ventricular wall thickness and longitudinal strain. However, the four Patents are directed to methods of treating amyloidosis. The prior art teaches treatment of amyloidosis reduces reduce the mean left ventricular wall thickness and longitudinal strain. See the evidence of CLEVELAND CLINIC JOURNAL OF MEDICINE (VOLUME 84 • SUPPLEMENT 3 DECEMBER 1, 2017, pages 1-26). A person of ordinary skill in the art would reasonably expect the methods of treating amyloidosis as taught by the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent to reduce the mean left ventricular wall thickness and longitudinal strain, absent evidence to the contrary.
The nonstatutory double patenting rejections of record are maintained. The alleged unexpected properties discussed in the Robbie Declaration are merely anticipated improvements reasonably expected by a person of ordinary skill in the art based on the teachings, suggestion and motivation of the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent. The evidence provided in the Robbie Declaration does not rise to the level of unexpected results. While the Examiner appreciates the data provided in the Declaration, there is no sufficient factual basis to explain why a person of ordinary skill in the art would find any of the results surprising. Furthermore, the alleged unexpected results were obtained through routine experimentation and obvious to try within a finite number of identified, predictable solutions, making the results expected.
The administration of the specific fixed dose of about 25 mg to about 50 mg taught and suggested by the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent are obvious variations of the Patent inventions made during the course of routine optimization. The results and evidence provided in the Robbie Declaration are what would be reasonably expected by the skilled artisan.
Substantial evidence supports the Examiner’s finding that the claims are obvious over the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent in view of Vinik et al. and evidenced by Merlini et al. and CLEVELAND CLINIC JOURNAL OF MEDICINE VOLUME. Turning to the facts, the presumption of obviousness applies here, and none of the means for rebutting it has been shown. In view of the foregoing, when all the evidence is considered, the totality of the rebuttal evidence of non-obviousness fails to outweigh the evidence of obviousness made of record. Thus, it is maintained that the invention as a whole would have been prima facie obvious to one of ordinary skill in the art before the effective filing date of the claimed invention.
Terminal Disclaimers disclaiming the terminal portion of any patent granted on this application which would extend beyond the expiration date of the ‘307 Patent, the ‘501 Patent, the ‘486 Patent and the ‘628 Patent are required, or some other appropriate action.
Conclusion
No claims are allowed at this time.
Any comments considered necessary by Applicant must be submitted no later than the payment of the issue fee and, to avoid processing delays, should preferably accompany the issue fee. Such submissions should be clearly labeled “Comments on Statement of Reasons for Allowance.”
Any inquiry concerning this communication or earlier communications from the Examiner should be directed to Terra C. Gibbs whose telephone number is 571-272-0758. The Examiner can normally be reached from 8 am - 5 pm M-F.
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/TERRA C GIBBS/Primary Examiner, Art Unit 1635