FINAL REJECTION
Receipt is acknowledged of Applicant's Amendments and Remarks, filed Nov. 10, 2025.
Rejections and/or objections not reiterated from previous Office Actions are hereby withdrawn. The rejections and/or objections set forth below are either maintained or newly applied, and constitute the complete set presently applied to the instant claims.
STATUS OF THE CLAIMS
Claim 4 has been canceled.
Claim 1 has been amended and incorporates no new matter.
Claims 5-7 have been amended to remove dependencies upon canceled claims.
No new claims have been added.
Thus, claims 1-3 and 5-23 now represent all claims currently pending and under consideration.
INFORMATION DISCLOSURE STATEMENT
No new Information Disclosure Statements (IDS) have been submitted.
WITHDRAWN REJECTIONS
Applicant's amendments overcome the rejections under 35 U.S.C. 102(a)(1) over Zeng et al. (US Pub. 2018/0280392) and Wu et al. (CN 105748435), which are withdrawn.
Applicant timely filed a proper terminal disclaimer, which was approved on Nov. 10, 2025. Thus, the provisional nonstatutory double patenting rejection over copending Application No. 18/246,463 is withdrawn.
MAINTAINED REJECTIONS
The following rejection is maintained from the previous Office Action dated Aug. 12, 2025, on the ground that the references cited therein continue to read on the limitations of the amended claims.
Claim Rejections - 35 USC § 103
Claims 1-3 and 5-23 stand rejected under 35 U.S.C. 103 as being unpatentable over Zeng et al. (US 2018/0280392), Wu et al. (CN 105748435), and Vivancos-Martinez et al. (WO 2019/020715).
Zeng et al. disclose pharmaceutical compositions comprising palbociclib or a hydrochloride or isethionate salt thereof, and dosage forms thereof, e.g., tablets or capsules, both having good stability and excellent dissolution performance.
In particular, Zeng et al. exemplify the composition of Formula 16 (Example 4), comprising palbociclib isethionate, microcrystalline cellulose + lactose (diluents), crosslinked sodium carboxymethyl cellulose, a.k.a. croscarmellose sodium (a disintegrant), and magnesium stearate (a lubricant), in amounts falling within the ranges recited by claims 1, 8-12, and 16-18, as shown in the table below.
Zeng et al. also exemplify the composition of Formula 29 (Example 7), comprising the same components as Formula 16, plus colloidal silicon dioxide (a glidant), in amounts falling within the ranges recited by claims 1 and 9-18, as shown in the table below.
Component
Zeng et al.
Formula 16
Zeng et al.
Formula 29
Claims 1 and 8-18
Palbociclib isethionate
35.7%
27.4%
25-50%; 30-45%
Diluent/Filler
(microcrystalline cellulose + lactose)
53.3%
56.6%
40-70%; 50-60%
Disintegrant (croscarmellose sodium)
5%
5%
1-15%; 3-10%
Glidant (colloidal silica, a.k.a. silicon dioxide)
--
2%
0-10%; 0.5-5%
Lubricant (Mg stearate)
1%
1%
0.1-10%; 0.5-4%
The composition of Formula 16 is disclosed to have a release rate of 95% at 15 minutes,
(Example 4, para. [0055]), which reads on the dissolution profiles (greater than or equal to 85% at 15 minutes, and greater than or equal to 60% at 60 minutes) as recited by claims 2, 3, and 22:
PNG
media_image1.png
118
496
media_image1.png
Greyscale
The composition of Formula 29 is disclosed to have a release rate of 95% at 15 minutes (Example 7, para. [0067]), which reads on the dissolution profiles (greater than or equal to 85% at 15 minutes, and greater than or equal to 60% at 60 minutes) as recited by claims 2, 3, and 22:
PNG
media_image2.png
138
496
media_image2.png
Greyscale
The compositions of Zeng et al. are not explicitly disclosed, after granulation, to have a tap density of 0.55-0.72 g/mL, or 0.62-0.69 g/mL, and an angle of repose of less than or equal to 44°, as recited by claims 19-21.
However, Zeng et al. claim methods of preparing the compositions by wet granulation (claim 11) or dry granulation (claim 12); thus, the compositions are granulated, and comprise identical components in identical amounts. Products of identical chemical composition cannot have mutually exclusive properties. A chemical composition and its properties are inseparable. Therefore, if the prior art teaches the identical structure, the properties applicant discloses and/or claims are necessarily present. In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
In addition, as recognized by MPEP §2112.01, where the claimed and prior art products are identi-cal or substantially identical in structure or composi-tion, or are produced by identical or substantially identical processes, a prima facie case of either antici-pation or obviousness has been established. In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977).
In summary, Zeng et al. exemplify compositions comprising palbociclib isethionate, microcrystalline cellulose + lactose (diluents), crosslinked sodium carboxymethyl cellulose, a.k.a. croscarmellose sodium (a disintegrant), colloidal silicon dioxide (a glidant), and magnesium stearate (a lubricant), in amounts falling within the ranges recited by claims 1 and 9-18; having dissolution profiles that read on claims 2, 3, and 22.
Similarly, Wu et al. exemplify a composition comprising palbociclib isethionate, a diluent (microcrystalline cellulose + lactose), a disintegrant (sodium starch glycolate, a.k.a. sodium carboxymethyl starch), a glidant (colloidal silicon dioxide), and a lubricant (magnesium stearate), with a particle size D90 of 94 μm (Example 5).
As shown in the table below, the composition of Wu et al. Example 5 comprises the identical components in amounts falling within the ranges recited by claims 1 and 8-18:
Component
Wu et al. (CN 105748435)
Example 5; claims 1-9
Claims 1 and 8-18
Palbociclib isethionate
35.6%
25-50%; 30-45%
Diluent/Filler
(microcrystalline cellulose + lactose)
56%
40-70%; 50-60%
Disintegrant (sodium carboxymethyl starch)
8%
1-15%; 3-10%
Glidant (colloidal silicon dioxide)
2.4%
0-10%; 0.5-5%
Lubricant (magnesium stearate)
2%
0.1-10%; 0.5-4%
Further, Wu et al. claim weight ranges for each component, as follows: the filler or diluent (e.g., microcrystalline cellulose and lactose) is 57-65% of the total weight of the composition; the disintegrant (e.g., sodium carboxymethyl starch) is 3-8% of the total weight of the composition; the glidant (e.g., colloidal silicon dioxide, silicon dioxide, or talc) is 1-4% of the total weight of the composition; and the lubricant (e.g., magnesium stearate or sodium stearyl fumarate) is 0.5-4% of the total weight of the composition (claims 2-9), all of which lie inside the ranges recited by claim 1.
The compositions of Wu et al. (Examples 1-11) are disclosed to have a release rate of greater than 95% in 15 minutes when tested in 900 mL of 0.1 M hydrochloric acid medium at 50 rpm using the Chinese Pharmacopoeia 2015 dissolution determination method (paras. [0086]-[0088]; Table 1), which reads on claims 2, 3, and 22.
In summary, Wu et al. exemplify a composition comprising palbociclib isethionate, a diluent (microcrystalline cellulose + lactose), a disintegrant (sodium starch glycolate, a.k.a. sodium carboxymethyl starch), a glidant (colloidal silicon dioxide), and a lubricant (magnesium stearate), in amounts falling within the ranges recited by claims 1 and 8-18; having a dissolution profile that reads on claims 2, 3, and 22, and a particle size D90 of 94 μm (Example 5).
Wu et al. further disclose that moderate particle size and good fluidity is obtained by controlling the recrystallization process of the raw material medicine (para. [0010]), wherein the particle size of the palbociclib or salt thereof, e.g., isethionate, is 50 μm to 150 μm (para. [0015]; claim 1). Thus, Wu et al. explicitly teach that the particle size of palbociclib isethionate is controlled in a synthesis process of the raw material of the palbociclib isethionate, as recited by claims 6 and 7.
While Wu et al. do not expressly disclose palbociclib isethionate with a particle size (D90) of 3-30 μm, as recited by amended claim 1, and Zeng et al. is silent as to particle size, the claimed palbociclib particle sizes were nonetheless known in the prior art.
Vivancos-Martinez et al. disclose pharmaceutical granulate compositions comprising crystalline palbociclib and pharmaceutically acceptable excipients, in particular exemplifying and claiming compositions comprising nearly identical components in identical amounts to those exemplified by Zeng et al. and Wu et al., and as recited by the instant claims (Example 2; claim 10). The prior art compositions are compared to the claimed compositions in the table below:
Component
Zeng et al.
Formula 29
Wu et al.
Ex. 5; claims 1-9
Vivancos-Martinez et al. (Example 2; claim 10)
Claims 1, 8-18
Palbociclib
27.4%
palbociclib isethionate
35.6%
palbociclib isethionate
27.8%; 25-35% palbociclib
free base
25-50%; 30-45%
Diluent/Filler
(MCC + lactose)
56.6%
56%
57%; 30-50% MCC + 12-30% lactose
40-70%; 50-60%
Disintegrant
5% cros-carmellose sodium
8% cros-carmellose sodium
3%; 2-4% sodium starch glycolate
1-15%; 3-10%
Glidant (colloidal silicon dioxide)
2%
2.4%
2.3%; 0.05-5% glidant + lubricant
0-10%; 0.5-5%
Lubricant
(Mg stearate)
1%
2%
2%; 0.05-5% glidant + lubricant
0.1-10%; 0.5-4%
The compositions of Vivancos-Martinez et al. differ from the claimed compositions in that they comprise palbociclib free base as the active pharmaceutical ingredient (API), rather than the isethionate salt.
However, like Zeng et al., the compositions of Vivancos-Martinez et al. are prepared by dry granulation (pp. 9-10), thus taking the form of granules, wherein the palbociclib crystals have a particle size distribution d(0.9) (D90) between 5 and 50 μm (p. 2, lines 13-17; claim 1). More preferably, the palbociclib particle size is from 7 to 30 μm (p. 3, lines 18-21), which overlaps the range of 3-30 μm, as recited by amended claim 1, and the range of 3-20 μm, as recited by claim 5, as shown in the table below:
Component
Zeng et al.
Wu et al.
Ex. 5 and 10; claim 1
Vivancos-Martinez et al. (Claim 1)
Claims 1, 5-7
and 23
Particle size
--
50 μm to 150 μm
5 μm to 50 μm
3-30 μm or
3-20 μm
As recognized by MPEP § 2144.05 (I), in the case where the claimed ranges “overlap or lie inside ranges disclosed by the prior art,” a prima facie case of obviousness exists. In re Wertheim, 541 F.2d 257, 191USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575,16 USPQ2d 1934 (Fed. Cir. 1990).
Because Zeng et al., Wu et al., and Vivancos-Martinez et al. disclose, teach, and suggest each and every element of the claimed compositions, it would have been predictable to one of ordinary skill in the art as of the effective filing date to modify the palbociclib isethionate compositions of Zeng et al. and Wu et al. by optimizing the particle size to within 3-30 μm, as taught by Vivancos-Martinez et al., with a reasonable expectation of success.
The rationale to combine the references is premised on the findings that (1) the prior art includes each ele-ment claimed, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference; (2) one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each ele-ment merely performs the same function as it does separately; and (3) one of ordinary skill in the art would have recognized that the results of the combi-nation were predictable. See MPEP § 2143 and KSR Int'l Co. v. Teleflex Inc. (550 U.S. 398, 409).
RESPONSE TO ARGUMENTS
Applicant's arguments filed Nov. 10, 2025 have been fully considered but they are not persuasive.
With respect to the rejection under 35 U.S.C. § 103 over Zeng et al., Wu et al., and Vivancos-Martinez et al., Applicant argues that the distinguishing technical feature of amended claim 1 is a particle size D90 of 3-30 µm, which solves the problem of the restriction that palbociclib must be administered after meals (Remarks dated 11/10/2025, p. 5).
Applicant asserts that the present invention surprisingly discovered that when palbociclib is prepared as palbociclib isethionate and its particle size is controlled within the range of 3-30 µm, the restriction that palbociclib must be administered after meals can be overcome. Experiments found that the release rate of palbociclib isethionate with a particle size of 3-30 µm at pH 6.8 can be increased, enabling high dissolution of palbociclib isethionate also in the intestine, achieving drug efficacy whether administered before or after meals. Neither Wu et al. nor Zeng et al. solve this technical problem (Remarks, p. 6).
Applicant acknowledges that Wu et al. recognize the technical problem of the low solubility of palbociclib in solutions with a pH >4.0, having a gastric residence time of 1.5-2 hours. Wu et al. teach that the dissolution rate in the stomach is critical, as it determines the drug's bioavailability: a slow dissolution rate shortens the absorption time of the drug in the stomach, potentially affecting clinical efficacy (Wu et al., para. [0093]). Consequently, in clinical practice, palbociclib is typically taught to be administered after meals (Remarks, p. 5).
However, Applicant argues that Wu et al. solve the technical problem of the dissolution rate of the palbociclib drug in the stomach by "controlling the raw material particle size of palbociclib, combined with the use of excipients with good fluidity, screening a reasonable formulation ratio, and adopting the process of directly mixing the raw and auxiliary materials and filling capsules." Thus, Applicant contends that Wu et al. increase the dissolution rate of palbociclib in the stomach within the original framework of post-meal administration; i.e., WU et al. does not break through the limitation of only being administerable after meals. Further, Wu et al. provide no suggestion that controlling particle size could achieve the goal of pre-meal administration or improving its dissolution at pH 6.8 (Remarks, p. 6).
Similarly, Applicant contends that Zeng et al. also do not teach that controlling the particle size of palbociclib isethionate within the range of 3-30 µm can improve the release rate of palbociclib isethionate in the composition at pH 6.8, thereby enabling it to no longer be subject to the restriction of post-meal administration (Remarks, p. 6).
Applicant further contends that, while Vivancos-Martinez et al. disclose a palbociclib particle size of 5-50 µm, palbociclib is in the free base form, which must be administered after meals because it has high dissolution in gastric fluid (pH 1.2) but very low dissolution in the intestine, greatly reducing its efficacy. Vivancos-Martinez measure dissolution at pH 2, which means that the composition in Vivancos-Martinez can also only be administered after meals, and not before meals (Remarks, pp. 6-7).
Applicant contends that results presented in the disclosure demonstrate that, at pH 1.2, palbociclib isethionate with D90 particle sizes of 3-120 µm have a high release rate (FIG. 1); whereas at pH 6.8, palbociclib isethionate has a high release rate (at or above 60%) only when the D90 particle size is 3-60 µm (FIG. 2) (Remarks, pp. 7-9).
Applicant contends that this demonstrates the unexpected technical effects achieved by the claimed compositions. Because the release rate at pH 6.8 is over 60% (as in Example 1 and Figure 2), and the release rate at pH 1.2 is over 85% (as in Example 1 and Figure 1), the claimed particle sizes achieve true equivalence under neutral and acidic conditions, so that patients do not need to consider the effect of administration before or after meals (Remarks, p. 9).
In summary, Applicant argues that the claimed compositions possess an advantage not recognized in the prior art: the particle size D90 of 3-30 μm improves the drug release rate and bioavailability so that the compositions are not limited to post-prandial administration.
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 are not recited in the rejected claims. The claims are drawn to compositions, not methods of treatment, and are silent as to the timing of administration (before or after meals). 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).
In addition, the fact that the inventor has recognized another advantage which would flow naturally from following the suggestion of the prior art cannot be the basis for patentability when the differences would otherwise be obvious. See Ex parte Obiaya, 227 USPQ 58, 60 (Bd. Pat. App. & Inter. 1985).
To establish a prima facie case of obviousness, there is no requirement that the prior art must recognize the same advantages or solve the same problem as the claimed invention. The focus is on whether the claimed invention as a whole would have been obvious, regardless of the inventor's purpose. "Treating the advantage as the invention disregards the statutory requirement that the invention be viewed ‘as a whole’" (Jones v. Hardy, 727 F.2d 1524, 1530, 220 USPQ 1021, 1026 (Fed. Cir. 1984)).
As recognized by MPEP § 2144 (IV), it is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant. See, e.g., In re Kahn, 441 F.3d 977, 987, 78 USPQ2d 1329, 1336 (Fed. Cir. 2006)).
Finally, in response to applicant's arguments against the references individually, one cannot show nonobviousness by attacking references individually where the rejection is based on a combination 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). Applicant offers no reason why a skilled artisan would not or could not have combined the teachings of the cited references with a reasonable expectation of success, e.g., by employing the isethionate salt of palbociclib as taught by Zeng et al. and Wu et al., in the methods of Vivancos-Martinez et al.
Fore the foregoing reasons, the rejection under 35 U.S.C. § 103 over Zeng et al., Wu et al., and Vivancos-Martinez et al. is maintained.
NEW REJECTIONS
Claim Rejections – 35 USC § 112(d) – Improper Dependency
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claim 23 is rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Specifically, claim 23 indirectly depends from claim 1, which has been newly amended to limit the palbociclib isethionate particle size D90 to 3-30 μm.
However, claim 23 recites a palbociclib isethionate particle size D90 of 3-60 μm, and thus fails to further limit the subject matter of the claim upon which it depends.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
CONCLUSION
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.
CORRESPONDENCE
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SARA E. TOWNSLEY whose telephone number is 571-270-7672. The examiner can normally be reached on Mon-Fri from 9:00 am to 6:00 pm (EST). If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Jeff S. Lundgren, can be reached at 571-272-5541. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/SARA ELIZABETH TOWNSLEY/Examiner, Art Unit 1629
/JEFFREY S LUNDGREN/Supervisory Patent Examiner, Art Unit 1629