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
New: 47-49
Examined Herein: 32-49
Priority
Acknowledgment is made of applicant's claim for priority under based upon an application filed in PRO 63/078,067 filed on 9/14/2020, PRO 63/227,180 filed on 7/29/2021, PRO 63/241,999 filed on 9/8/2021, and PCT/US2021/050091 filed on 9/13/2021.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 11/27/2023, 12/3/2024, 10/28/2025, and 3/23/2026 is in compliance with the provisions of 37 CFR 1.97. Accordingly, the information disclosure statement is being considered by the examiner.
Drawings
The drawings received on 3/7/2023 are accepted.
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 32-48 are rejected under 35 U.S.C. 103 as being unpatentable over Sun (US 2019/0083448 A1, Published 3/21/2019), in view of Desai (US 2007/0117744 A1, Published 5/24/2007).
With respect to claim 32, Sun discloses a composition (Example 1) comprising cabazitaxel, methanol, human serum albumin (HSA), and a parenterally acceptable vehicle, water. [Sun, 0425-0426] The composition disclosed by Sun does not contain a surfactant.
With respect to claim 33, Sun discloses the composition comprises 4 mg cabazitaxel, 10 mL methanol, and 1.2 g HSA. [Sun, 0425-0426]
With respect to claim 39, Sun discloses the composition is a clear, or transparent, solution free of visible particles or precipitates. [Sun, 0077, 0425-0426]
With respect to claim 40, Sun discloses the composition stays a clear, or transparent, solution free of visible particles or precipitates for about 24 hours. [Sun, 0426]
With respect to claims 44-46, Sun discloses the composition was filtered through a 0.22 µm aqueous phase filter. [Sun, 0425] Therefore, the composition does not comprise particles greater than 0.22 µm in size. [Sun, 0103]
Also, with respect to claim 32, Sun discloses a composition (Example 14) comprising cabazitaxel, methanol, human serum albumin (HSA), and a parenterally acceptable vehicle, water. [Sun, 0469]
With respect to claim 39, Sun discloses the composition is a clear, or transparent, solution free of visible particles or precipitates. [Sun, 0077, 0469]
With respect to claim 41, Sun discloses the concentration of cabazitaxel in the composition is about 0.2 mg/mL. [Sun, 0469] (This value was obtained by the following calculation: Concentration of cabazitaxel (mg/mL) = 20 mg cabazitaxel ÷ (28.3 mL methanol + 66 mL water) = ~0.212 mg/mL).
With respect to claim 42, Sun discloses the concentration of HSA in the composition is about 5% w/v. [Sun, 0469] (This value was obtained by the following calculation: Concentration of HSA = (mass of solute (g) ÷ volume of solution mL) × 100% = 5 g HSA ÷ (28.3 mL methanol + 66 mL water) × 100% = 5.3 % w/v).
With respect to claim 43, Sun discloses the pH value of the composition is about 6.8. [Sun, 0481]
Sun does not disclose that either composition comprises citric acid or ethanol, wherein the weight ratio of cabazitaxel and citric acid is from about 5000:1 to about 1:1. (Claim 32) Sun does not disclose that the composition (Example 1) comprises ethanol. (Claim 33) Sun does not disclose that at least 10% or 30% of the cabazitaxel in either composition is free (unbound in solution). (Claim 36 & 37) Sun does not disclose that the weight ratio of cabazitaxel and citric acid is from about 2000:1 to about 20:1, about 700:1 to about 20:1, or about 200:1. (Claim 47-49)
However, with respect to claims 32 and 33, Sun discloses that cabazitaxel is dissolved in a polar organic solvent (e.g., an alcohol such as methanol, ethanol, isopropanol, and/or n-butanol; THF, CH3CN; DMF; or mixtures thereof) to form an organic solution. [Sun, 0349, 0352, 0405, 0406] Sun further discloses, in some embodiments, the amount of polar organic solvent is from about 0.05 mL to about 50 mL per mg of cabazitaxel. [Sun, 0353]
Also, with respect to claim 32, Sun discloses that the comporision may further comprise bacteriostats. [Sun, 0081]
With respect to claim 36 and 37, Sun discloses that, in some embodiments, the amount of cabazitaxel that is bound to the HSA in the aqueous solution is at least 40-100%. [Sun, 0102] This teaching implies that about 0-60% of cabazitaxel in the composition is free (unbound in solution).
Moreover, with respect to claim 32, Desai discloses a composition comprising a taxane, an albumin, and an antimicrobial agent, including citrate (or citric acid). [Desai, 0014, 0046] Desai discloses the antimicrobial agent is effective against the growth of one or more bacteria. [Desai, 0037, 0041] Desai further discloses a suitable concentration for citric acid is 0.1 mg/mL to 200 mg/mL or the weight ratio of the citrate to the taxane is 0.02:1 to about 40:1. [Desai, 0046]
Modifying the composition (Example 1) disclosed by Sun by adding ethanol to the composition in an amount wherein the polar organic solvent does not exceed about 50 mL per mg of cabazitaxel, and by adding citric acid in an amount wherein the weight ratio of cabazitaxel to citric acid is 1:0.02 to about 1:40, results in the composition of claim 32, wherein the composition comprises:
4 mg cabazitaxel
10 mL methanol
> 0 – 190 mL ethanol
0.08 – 160 mg citric acid
1.2 g HSA,
22mL of water, and
wherein the weight ratio of cabazitaxel and citric acid is 0.025 - 50:1.
Accordingly, with respect to claim 33, the composition comprises about 5 mg of cabazitacel, 0.5 mL to 15 mL of ethanol, and 1.2 g of HSA.
Modifying the composition (Example 14) disclosed by Sun by adding ethanol to the composition in an amount wherein the polar organic solvent does not exceed about 50 mL per mg of cabazitaxel, by adding citric acid in an amount wherein the weight ratio of cabazitaxel to citric acid is 1:0.02 to about 1:40, results in the composition of claim 32, wherein the composition comprises:
20 mg cabazitaxel
28.3 mL methanol,
> 0 – 971 mL ethanol
0.4 mg – 800 mg citric acid
5 g HSA, and
66 mL of water, and
wherein the weight ratio of cabazitaxel and citric acid is 0.025:1 - 50:1.
Accordingly, with respect to claim 33, the composition comprises 20 mg of cabazitaxel, 0.5 mL to 15 mL of ethanol, and 5 g of HSA.
With respect to claim 47 and 48, the weight ratio of cabazitaxel and citric acid in both compositions (Example 1 and 14) is 0.025:1 to 50:1.
Further modifying both compositions disclosed by Sun so that 0-60% of cabazitaxel in the composition is free (unbound in solution) results in the composition of claim 36 and 37.
It would be obvious to one of ordinary skill in the art to modify the composition disclosed by Sun by adding ethanol to the composition in an amount wherein the polar organic solvent does not exceed about 50 mL per mg of cabazitaxel and have a reasonable expectation of success. Sun discloses a composition comprising cabazitazel and a polar organic solvent, methanol. Sun further discloses the polar organic solvent of the composition may be a mixture of methanol and ethanol, wherein the amount of polar organic solvent is from about 0.05 mL to about 50 mL per mg of cabazitaxel. In view of this express teaching by Sun, it is reasonable to expect the composition may be modified by adding ethanol to the composition in an amount wherein the polar organic solvent does not exceed about 50 mL per mg of cabazitaxel. One would have been motivated to do so because it is prima facie obvious to combine equivalents known for the same purpose. MPEP 2144.06(I). In the present case, Sun discloses both methanol and ethanol are polar organic solvents, thereby recognizing them as functional equivalents, and further discloses a mixture thereof is suitable for use in the composition. Therefore, one of ordinary skill in the art would be motivated to combine one polar organic solvent, methanol, with another polar organic solvent, ethanol.
It would be obvious to one of ordinary skill in the art to modify the composition disclosed by Sun by adding citric acid in an amount wherein the weight ratio of cabazitaxel to citric acid is 1:0.02 to about 1:40 and have a reasonable expectation of success. Sun discloses a composition comprising a taxane, cabazitaxel, and HSA. Sun further discloses the composition comprises bacteriostats. Desai discloses a composition comprising a taxane, an albumin, and an antimicrobial agent, citric acid. Desai discloses the antimicrobial agent is effective against growth of one or more of bacteria at a concentration wherein the weight ratio of the citric acid to the taxane is 0.02:1 to about 40:1. Accordingly, Desai establishes that citric acid may effectively function as a bacteriostat in a composition comprising a taxane and albumin the weight ratio of the citric acid to the taxane is 0.02:1 to about 40:1. Therefore, the combined teachings of Sun and Desai reasonably suggest that citric acid may effectively function as a bacteriostat in the composition comprising a taxane, cabazitaxel, and HSA, disclosed by Sun at a weight ratio of the citric acid to the taxane is 0.02:1 to about 40:1. One would have been motivated to do so because it is prima facie obvious to modify a prior art reference when some teaching, suggestion, or motivation in the prior art would have led one of ordinary skill to do so. MPEP 2144(I). In the present case, Desai discloses citric acid may be effective against the growth of one or more bacteria for at least about 4 to 120 hours, and capable of retarding the growth of microorganisms in the composition to no greater than about 1 log increase (10-fold) in about 24 hours after extrinsic contamination. [Desai, 0037-0041] Therefore, one would have been motivated by the expectation that the addition of citric acid to the composition disclosed by Sun would effectively inhibit and retard bacterial growth in the composition.
It would be obvious to one of ordinary skill in the art to modify the composition disclosed by Sun so that 40-60% of cabazitaxel in the composition is free (unbound in solution) and have a reasonable expectation of success. Sun discloses an aqueous solution comprising cabazitaxel and HSA. Sun further discloses that, in some embodiments, the amount of cabazitaxel bound to the HSA is at least 40-100%, implying that 0-60% of cabazitaxel in the composition is free. In view of this implicit teaching, it is reasonable to expect the composition disclosed by Sun may be modified so that 0-60% of cabazitaxel in the composition is free. One would have been motivated to do so because it is prima facie obvious to modify a prior art reference when some teaching, suggestion, or motivation in the prior art that would have led one of ordinary skill to do so. MPEP 2144(I). In the present case, Sun implicitly discloses that in one embodiment, 0-60% of cabazitaxel in the composition is unbound in solution. Therefore, one of ordinary skill in the art would have been motivated to modify the composition so that the fraction of free cabazitaxel falls within the range suggested by the prior art.
Claim 32 recites the limitation “wherein the infusion composition is prepared by injecting a liquid composition comprising cabazitaxel, ethanol and citric acid into an infusion bag or bottle containing an aqueous composition comprising human serum albumin in a parenterally acceptable vehicle, wherein mixing of the liquid composition and the aqueous composition is done in an infusion bag/bottle,” which is a product by process limitation. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." MPEP 2113(I). In the instant case, the claimed product is obvious in view of the product disclosed by Sun and Desai. Therefore, the claim is unpatentable even if the product disclosed by Sun and Desai was made by a different process. Furthermore, while the limitation “contained in an infusion bag/bottle” does not itself recite a process, it is material to the preparation process rather than to the product. In other words, the product is placed in an infusion/bottle bag as a part of the preparation process. Accordingly, for the same reasons described above, this limitation is also unpatentable.
Claims 34, 35, 38, and 46 recite limitations that merely narrow the product by process limitation defined above. For the same reasons described above, the claim is unpatentable even if the product disclosed by Sun and Desai was made by a different process. Accordingly, since the patentable limitations of claim 32 are obvious over Sun and Desai, the limitations of claim 34, 35, 38, and 46 are also obvious over Sun.
Claims 32-49 are rejected under 35 U.S.C. 103 as being unpatentable over Sun and Desai, as applied to claims 32-48 above, and further in view of Malhotra (US 2017/0119726 A1, Published 5/4/2017).
With respect to claim 32 and 47, Sun and Desai disclose the teachings above.
Sun and Desai do not disclose that the weight ratio of cabazitaxel and citric acid in either composition (Example 1 or 14) is 700:1 to about 200:1.
However, with respect to claim 49, generally, differences in concentration will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. Where the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation. MPEP 2144.05(II). In the present case, the general conditions of the claim are described by Sun and Desai as explained above. Therefore, it is not inventive to discover the optimum or workable weight ratio of cabazitaxel to citric acid by routine experimentation.
It would have been routine optimization to arrive at the claimed invention because the amount of citric acid required in a cabazitaxel formulation is a result-effective variable, as the amount present correlates with the relative strength of the acid. Malhotra discloses a composition comprising cabazitaxel as the active ingredient. Malhotra further discloses the composition may comprise citric acid. [Malhotra, 0074-0075] Malhotra states that a person skilled in the art will know that certain strong acids may react with cabazitaxel, creating degradants, and to avoid such acids. For example, epimerization of the hydroxyl functionality of cabazitaxel is known to be facilitated by certain strong acids. [Malhotra, 0074-0075] Thus, the optimum range of cabazitaxel to citric acid influences the reaction between the two compounds and potentiates the creation of degradants. Therefore, it would have been routine optimization to optimize the weight ratio of cabazitaxel and citric acid in either composition (Example 1 or 14) to optimize the reaction between the two compounds and minimize the creation of degradants.
A person of ordinary skill in the art would have had a reasonable expectation of success to formulate the claimed range because Desai discloses, in some embodiments, the weight ratio of citric acid to the taxane is less than 0.1:1. Therefore, a POSITA would have been motivated to formulate the weight ratio of citric acid to the taxane to less than 0.1:1, including, for example, 0.01:1 or 0.001 to 1 or 0.0001:1. In which case, a POSITA would successfully formulate the claimed weight ratio of cabazitaxel to citric acid (10:1 to 10000:1). [Desai, 0046]
Response to Arguments
Applicant's arguments, filed 6/11/2026, have been fully considered but they are not persuasive.
Applicant asserts “However, Sun does not make any connection between the use of citric and parenteral administration. Parenteral administration is referred to in Sun in certain "boilerplate" paragraphs, but Sun does not say that citric acid (or any other buffer) would be suitable for parenteral administration.” [Remarks 6/11/2026, Page 6, Paragraph 2]
Sun makes a connection between the use of buffers and parenteral administration. Sun states: “Formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain…. buffers… that render the formulation compatible with the blood of the intended recipient…” [0126] Sun further states: “In some embodiments, the buffer comprises…. citric acid…” [0208] In view of the foregoing, it is reasonable to expect that the formulations suitable for parenteral administration include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain buffers that comprise citric acid and that render the formulation compatible with the blood of the intended recipient.
[I]n considering the disclosure of a reference, it is proper to take into account not only specific teachings of the reference but also the inferences which one skilled in the art would reasonably be expected to draw therefrom. MPEP 2144.01. Sun does not need to explicitly draw a connection between the use of citric and parenteral administration because the connection can be logically inferred. Moreover, Sun does not disclose any teaching and the Applicant provides no reason why this inference is unreasonable.
Applicant asserts “Further, the Examiner's own language ("could confer compatibility ... ") implies that any effect of a buffer on the compatibility with the blood of the intended recipient would be a mere possibility, not a predictable effect.” [Remarks 6/11/2026, Page 6, Paragraph 2]
The phrase “could” was intended to account for the fact that Office does not claim to guarantee that citric acid buffers would render the formulation compatible with the blood of the intended recipient. The Examiner used the phrase to acknowledge that the prima facie case is rebuttable.
Applicant asserts “Parenteral administration is referred to in Sun in certain "boilerplate" paragraphs, but Sun does not say that citric acid (or any other buffer) would be suitable for parenteral administration.” [Remarks 6/11/2026, Page 6, Paragraph 2]
Patents are relevant as prior art for all they contain. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. MPEP 2123(I). Even if, arguendo, parenteral administration is referred to in Sun in certain "boilerplate" paragraphs, those “boilerplate” paragraphs may be relied upon for all that they suggest to a POSITA.
Applicant asserts “Secondly, the Examiner states that Sun identifies citric acid as a buffer, and that "[i]t is well established that buffers stabilize compositions by maintaining a consistent pH. Therefore, it is not surprising that a buffer, such as citric acid, stabilizes cabazitaxel in organic solvents." Applicant respectfully disagrees for at least the following reasons. (i) Sun does not disclose citric acid itself as a buffer. Rather, paragraph [0081] of Sun states that the aqueous solution may be a buffer, and that the buffer may comprise citric acid, among other possible components. Thus, Sun discloses citric acid only as a possible component of an aqueous buffer system, not as a buffer by itself.” [Remarks 6/11/2026, Page 7, Paragraph 3-4]
While the Applicant’s point is acknowledged, the Applicant is drawing an unnecessary distinction. Both the Examiner and the Applicant’s interpretation of a buffer comprising citric acid is reasonable. This disclosure could refer to (1) a citric acid buffer or (2) a buffer comprising citric acid as a mere component. Sun provides no further teaching that would moot either interpretation. A reference may be relied upon for all that it would have reasonably suggested to one having ordinary skill in the art. MPEP 2123(I). Since a POSITA could reasonably interpret a buffer comprising citric acid as a citric acid buffer, then Sun may be relied on for this teaching.
Regardless, Sun further discloses “In some embodiments, the buffer is any one of buffers described, for example, in Y.-C. Lee et al. International Journal of Pharmaceutics 253 (2003) 111-119, the disclosure of which is incorporated herein by reference in its entirety.” [0081] Lee describes citric acid buffer. [Lee, Page 113, Table 2] Therefore, Sun provides an additional teaching that “a buffer comprising… citric acid” refers to citric acid buffer.
Applicant asserts “Sun therefore does not teach or suggest using citric acid together with cabazitaxel in ethanol, nor does Sun provide a reasonable expectation that citric acid would improve the chemical stability of cabazitaxel in such an ethanol-containing liquid composition, as discussed in (ii) below.” [Remarks 6/11/2026, Page 6, Paragraph 4]
The rejection of record does not claim that Sun suggests using citric acid together with cabazitaxel and ethanol. The instant rejection states that Sun discloses (1) that ethanol is a water-miscible organic solvent and may function as such in the composition and (2) a buffer comprising citric acid may be added to the aqueous solution. The instant rejection merely acknowledges that both modifications may occur and this assertion is fully supported by Sun. [Sun, 0014, 0016, 0233, 0304, 0349, 0352, 0015, 0081] Sun discloses both citric acid and ethanol as components that may be present in the composition. Sun does not suggest that ethanol and citric acid may be present only as alternatives. Moreover, Applicant has not provided any teaching in Sun suggesting that a formulation containing ethanol would exclude citric acid, or vice versa.
Applicant asserts “While buffers can, in certain amounts, stabilize the pH of compositions, they are not generally known to stabilize the active agent itself, as is the case here and as demonstrated, for example, in Example 13.” [Remarks 6/11/2026, Page 7, Paragraph 2]
Applicant’s arguments are not persuasive because buffers are known in the art to stabilize the active agent itself. This is evidenced by at least the following disclosures:
“The pH of the buffer is generally chosen to stabilize the active agent, and generally will be present at almost physiological pH...” [US 20040092470 A1, 0041]
“Most injectable pharmaceutical formulations contain a buffer to stabilize the pharmaceutically active agent against the chemical degradation that might occur if the pH changes appreciably.” [US 20070249522 A1, 0004]
“When the dry powder is prepared by solvent precipitation, buffers and salts are typically used to stabilize the active agent in solution prior to particle formation.” [US 20080234292 A1, 0118]
Conclusion
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 KAILA A CRAIG whose telephone number is (703)756-4540. The examiner can normally be reached Monday-Friday 0800-1600.
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/K.A.C./Examiner, Art Unit 1618
/Michael G. Hartley/Supervisory Patent Examiner, Art Unit 1618
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