DETAILED ACTION
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 .
Status of Claims
Claims 1-9, 28, 31-53, 59-64, 66, 69-70, and 72 are pending.
Priority
Instant application 18/710,701, filed 05/16/2024 claims priority as follows:
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Information Disclosure Statement
All references from IDS(s) received 05/16/2024 and 07/30/2026 have been considered unless marked with a strikethrough.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-9, 28, 31-37, and 59-64 in the reply filed on 07/30/2026 is acknowledged.
Claims 38-53, 66, 69, 70, and 72 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to nonelected inventions, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 07/30/2026.
Claim Objections
Claim 36 is objected to because of the following informalities: the phrase “of any other amorphous of tafamidis” in the last line of the claim contains a typographical error. Appropriate correction is required.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 1-9, 28, 31-37, and 59-64 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 1 recites “chemical shift differences between a reference peak at a reference peak at 70.0±0.2 ppm of: 91.8, 75.3, 62.5, 56.0, 50.3±0.1 ppm, respectively.” The phrase “differences between” renders claim 1 unclear. Additionally, claim 1 does not recite the direction of the differences (e.g., should 50.3 be added to 70.0, or subtracted?). See, for comparison, the language in claim 46, which is considered to be clear and definite:
Claim 1
Claim 46
a solid state 13C NMR spectrum having chemical shift differences between a reference peak at 70.0±0.2 ppm of: 91.8, 75.3, 62.5, 56.0, 50.3±0.1 ppm, respectively
a solid state 13C NMR spectrum having the following chemical shift absolute differences from a reference peak at 109.5 ppm±0.2 ppm of 62.1, 51.6, 39.6, 35.2, 21.5±0.1 ppm
In the interest of compact prosecution, the examiner recommends amending claim 1 to replace “differences between a reference peak” with “absolute differences from a reference peak”. Please also note for claim 1 that the term “respectively,” which ordinarily signals that the items in two separate lists connect to each other in the exact order they are written, is unclear because only one list is recited in (iii). Therefore, the term “respectively” should be removed.
In addition to the issue above, claim 1 is also indefinite because option (iii) defines the claimed tafamidis form by reference to chemical shift differences measured from “a reference peak at 70.0±0.2 ppm”, yet tafamidis does not exhibit a 13C signal at 70.0 ppm. For example, see FIG. 4 of the present Specification, which shows the 13C spectrum of anhydrous Form V of tafamidis having no signal upfield of 109.46 ppm.
The signal at 70.00 ppm appearing in FIG. 7 is attributable to polyethylene glycol (PEG-400), which is the crystallization medium used to prepare the claimed Form Va (see Examples 1, 2, and 6). The peaks at 62.39 and 73.39 ppm correspond to the terminal and second to last methylene group in PEG. See, for comparison, the 13C NMR spectrum of pure PEG-400 from FIG 1 of US 10,196,478 B2:
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The reference peak recited in option (iii) is apparently not a signal of tafamidis, but of a separate substance. It is therefore unclear whether option (iii) requires the presence of polyethylene glycol as a component of the claimed product. Is the disclosed form Va a co-crystal of PEG-400 and tafamidis? Or is the PEG-400 in FIG. 7 merely an impurity? Appropriate clarification is required.
Claims 2-9, 28, 31-37, and 59-64 depend from claim 1 and fail to resolve the issues identified above. Therefore, claims 2-9, 28, 31-37, and 59-64 are also indefinite.
Claims 6, 33, 35-37, and 64 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 6, 33, 35-37, and 64 recite the limitation “about”. The term “about” is a relative term which renders the claim indefinite. The term “about” is not defined by the claim, the specification does not provide a standard for ascertaining the requisite degree, and one of ordinary skill in the art would not be reasonably apprised of the scope of the invention. The meets and bounds of the claims are unclear because the term “about” introduces ambiguity to the numerical value following the term.
Claims 2-6 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 2 recites the limitation “an additional peak”. There is insufficient antecedent basis for this limitation in the claim. The term “additional” requires a set of peaks to which the recited peak is additional. Claim 1 recites the characterizing data in the alternative, and options (ii) and (iii) recite no XRPD peaks. Where claim 1 is satisfied by only options (ii) and/or (iii), there are no clear XRPD peaks to which the peak of claim 2 could be “additional”. A person of ordinary skill would not be able to determine from claim 2 whether a crystalline form satisfying claim 1 by option (ii), and exhibiting an XRPD peak at 5.8 degrees but lacking a peak at 13.3 degrees, falls within the scope of claim 2.
Claims 3-6 are indefinite for the same reasons articulated above.
For comparison, claim 7, which also depends from claim 1, recites that the crystalline form is “characterized by an X-ray powder diffraction pattern having peaks at 5.8, 9.5, 13.3, 13.7, 16.3, 19.7, 20.0, and 28.8”. Claim 7 recites the complete set of peaks required and does not rely on the term “additional”. The scope of claim 7 is therefore determinable without reference to which alternative of claim 1 was satisfied.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claims 1-6, 34-37, and 59 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by GIRARD (US 9,770,441 B1; cited in IDS).
Claim 1 is directed to a crystalline form of tafamidis, designated form Va, characterized by data selected from (i) recited XRPD peaks, (ii) recited 13C NMR peaks, or (iii) recited chemical shift differences from a reference peak.
Girard discloses crystalline tafamidis in polymorphic forms 1, 4, and 6. In view of the values of the peaks of the XRPD given with a margin of ± 0.2 degrees 2-Theta both in Girard and the instant claims, Forms 1, 4, and 6 disclosed by Girard anticipate the crystalline form recited in claims 1-6. See the analysis in the table below:
Claim No.
Claimed XRPD peak range
Girard XRPD peak range (Form 1)
Girard XRPD peak range (Form 4)
Girard XRPD peak range (Form 6)
1
13.1–13.5, 16.1–16.5, and 19.5–19.9
12.8–13.2, 16.3–16.7, and 19.2–19.6
13.0–13.4, 16.5–16.9, and 19.5–19.9
13.4–13.8, 16.1–16.5, and 19.1–19.5
2
5.6–6.0
-
-
5.8–6.2
3
9.3–9.7
9.5–9.9
9.6–10.0
-
4
13.5–13.9
13.9–14.3
13.9–14.3
-
5
19.8–20.2
20.0–20.4
19.5–19.9
20.2–20.6
6
28.6–29.0
28.4–28.8
-
-
With respect to claims 34-36, Girard discloses Forms 1, 4, and 6 having less than 1% by weight of any other forms of tafamidis (see Col. 4, lines 28-29; Col. 5, lines 63-64; and Col. 7, lines 18-29). Therefore claims 34-36 are anticipated by Girard.
With respect to claim 37, Girard discloses that Form 1 was analyzed by isothermal vapor sorption analysis and showed that Form 1 is anhydrous with less than 0.25% reversible weight gain, representing less than 0.25% of any organic solvent in the crystal structure (Col. 16, lines 1-9). Therefore, claim 37 is anticipated by Girard.
With respect to claim 59, Girard discloses pharmaceutical compositions comprising solid Form 1 or solid Form 4 and excipients (Col. 20, lines 26-35). Therefore, claim 59 is anticipated by Girard.
Claims 1-8, 32-33, and 59 are rejected under 35 U.S.C. 102(a)(2) as being anticipated by RAMASAMY (WO 2022009221 A1; filed 03 July 2021; cited in IDS).
Claim 1 is directed to a crystalline form of tafamidis, designated form Va, characterized by data selected from (i) recited XRPD peaks, (ii) recited 13C NMR peaks, or (iii) recited chemical shift differences from a reference peak.
The instant claims are being interpreted as encompassing crystalline salts of tafamidis. Claim 1, option (i), requires peaks at 13.3, 16.3, and 19.7 degrees two-theta ±0.2 degrees two-theta, representing permissible ranges of 13.1–13.5, 16.1–16.5, and 19.5–19.9 degrees two-theta respectively.
RAMASAMY discloses a crystalline diethanolamine salt of tafamidis characterized by an X-ray powder diffraction pattern having peaks at 13.4, 16.3, and 19.5 (Ramasamy, pages 14-15, Table 3). Each value disclosed by Ramasamy falls within the corresponding range of claim 1. Ramasamy discloses at page 22 that the diffraction data were obtained using CuKα radiation, consistent with the conditions disclosed at [00119] of the specification.
Claims 2-8, reciting additional XRPD peaks, are also anticipated. See the analysis in the table below:
Claimed XRPD peak range
Ramasamy Peaks in Table 3
Claim 1
13.1–13.5, 16.1–16.5, and 19.5–19.9
13.4, 16.3, 19.5
Claim 2
5.6–6.0
5.6
Claim 3
9.3–9.7
9.3
Claim 4
13.5–13.9
13.8
Claim 5
19.8–20.2
20.0
Claim 6
28.6–29.0
29.0
Claim 7
5.6–6.0, 9.3–9.7, 13.5–13.9, 19.8–20.2, and 28.6–30.0
5.6, 9.3, 13.8, 20.0, and 29.0
Claim 8
one or more peaks selected from: 23.1–23.5, 23.2–23.6, 23.5–23.9, 24.9–25.3, 26.4–26.8
23.3, 23.6, 25.1, 26.5
Therefore, claims 1-8 are anticipated by the Form in Ramasamy’s Table 3.
Ramasamy additionally discloses a crystalline meglumine salt of tafamidis characterized by an X-ray powder diffraction pattern disclosed in Ramasamy’s Table 7. In view of the values of the peaks of the XRPD given with a margin of ± 0.2 degrees 2-Theta both in Ramasamy and the instant claims, the crystal form of Ramasamy’s Table 7 anticipates the crystalline form recited in claims 1 and 4-6. See the analysis in the table below:
See the analysis in the table below:
Claimed XRPD peak range
Ramasamy Peaks in Table 7
Claim 1
13.1–13.5, 16.1–16.5, and 19.5–19.9
13.0–13.4, 16.4–16.8, 19.6–20.0
Claim 4
13.5–13.9
13.6-14.0
Claim 5
19.8–20.2
19.6-20.0
Claim 6
28.6–29.0
28.4-28.8
Therefore, claims 1 and 4-6 are anticipated by the Form in Ramasamy’s Table 7.
With respect to claims 32-33, Ramasamy discloses that the meglumine salt of tafamidis characterized in Table 7 is a hydrate having moisture content in the range of about 3.5% to about 9%, preferably about 5 to 7% (page 21, first paragraph). Therefore, claims 32-33 are anticipated by the Form in Ramasamy’s Table 7.
With respect to claim 59, Ramasamy discloses a pharmaceutical composition comprising the hydrate of tafamidis in admixture with at least one pharmaceutically acceptable excipient (Ramasamy claim 19). Therefore claim 59 is anticipated by Ramasamy.
Claim Rejections - 35 USC § 103
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, 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 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.
Claims 60-64 are rejected under 35 U.S.C. 103 as being unpatentable over RAMASAMY (WO2022009221A1; filed 03 July 2021) in view of PFIZER (“Highlights of Prescribing Information — VYNDAQEL and VYNDAMAX,” published May 2019, 16 pages) as evidenced by KIBBE (Handbook of Pharmaceutical Excipients, edited by Raymond C. Rowe et al., 6th ed., Pharmaceutical Press, 2009 pp. 581–86).
The teachings of Ramasamy are disclosed above and at least those teachings are incorporated herein by reference. Ramasamy discloses crystal forms anticipating instant claims 1-8, 32-33, and a pharmaceutical composition anticipating claim 59.
With respect to claims 60-64, Ramasamy discloses a pharmaceutical composition comprising the hydrate of tafamidis in admixture with at least one pharmaceutically acceptable excipient, but does not specify the identity of the excipients as recited by these claims.
However, the excipients recited in claim 60-64 are not new and have been previously used in formulations of tafamidis (VYNDAMAX) and tafamidis meglumine (VYNDAQEL). See, for example, the Pfizer reference, which discloses on page 5 the formulations of VYNDAMAX and VYNDAQEL and teaches excipients including PEG-400, the surfactant polysorbate 80 or polysorbate 20, povidone (K-value 90), and the non-ionic emulsifier sorbitan monooleate.
As evidenced by the Kibbe reference, povidone having a K-value of 90 has an approximate molecular weight of 1,000 kDa (Kibbe, page 581, Table 1) which reads on the ranges recited in claim 64.
Finding of prima facie obviousness
The Supreme Court in KSR Int'l Co. v. Teleflex Inc., 550 U.S. 398, 415-421, 82 USPQ2d 1385, 1395-97 (2007) identified a number of rationales to support a conclusion of obviousness which are consistent with the proper "functional approach" to the determination of obviousness as laid down in Graham. See MPEP 2143.
Examples of rationales that may support a conclusion of obviousness include:
(A) Combining prior art elements according to known methods to yield predictable results;
(B) Simple substitution of one known element for another to obtain predictable results;
(C) Use of known technique to improve similar devices (methods, or products) in the same way;
(D) Applying a known technique to a known device (method, or product) ready for improvement to yield predictable results;
(E) "Obvious to try" – choosing from a finite number of identified, predictable solutions, with a reasonable expectation of success;
(F) Known work in one field of endeavor may prompt variations of it for use in either the same field or a different one based on design incentives or other market forces if the variations are predictable to one of ordinary skill in the art;
(G) Some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to modify the prior art reference or to combine prior art reference teachings to arrive at the claimed invention.
Applying KSR example rationale (A) and/or (G), it would have been prima facie obvious to prepare a pharmaceutical composition comprising the crystal forms of tafamidis disclosed by Ramasamy and the pharmaceutical excipients recited by instant claims 60-64 in view of their having been taught in the Pfizer reference.
Accordingly, in view of the foregoing, claims 60-64 are obvious over Ramasamy in view of Pfizer as evidenced by Kibbe.
Conclusion
Claims 1-9, 28, 31-37, and 59-64 are rejected. Claims 38-53, 66, 69, 70, and 72 are withdrawn.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Kyle Nottingham whose telephone number is (571)270-0640. The examiner can normally be reached M-F from 10:00 am - 6:00 pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached at (571) 270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/K.N./Examiner, Art Unit 1621
/CLINTON A BROOKS/Supervisory Patent Examiner, Art Unit 1621
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