DETAILED ACTION
This office action is in response to the Applicant’s filing dated January 28th, 2026.
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 .
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 January 28th, 2026 has been entered.
Status of Claims
Claims 1, 3, 5-7, 10-15 and 19-20 are pending in the instant application. Acknowledgement is made of Applicant’s remarks and amendments filed on July 29th, 2025. Acknowledgment is made of Applicant’s amendment of claims 1 and 5-7; and cancelation of claims 2, 4, 8-9 and 16-18.
Priority
This application is a 371 of PCT/CN2021/077009 filed on February 20th, 2021; and claims benefit of foreign priority of CN202010107404.6 filed on February 21st, 2020.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claims 1, 3, 5-7, 10-11, 14-15 and 19 are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al (EP 3556369 A1), cited in a previous Office action; in view of Huang et al (US 2015/0182457 A1), cited in a previous Office action.
Regarding claims 1, 7, 10-11 and 19, Gan teaches Olaparib is an insoluble drug (page 4, paragraph [0015]). Gan further teaches a pharmaceutical composition in an improved dissolution form, specifically a solid dispersion; wherein the solid dispersion comprises Olaparib as an active ingredient, one or a combination of two or more matrix polymers (carriers) selected from a list comprising 2-hydroxypropyl-ß-cyclodextrin and copovidone, and a pharmaceutically acceptable surfactant; wherein based on the total weight of the solid dispersion the Olaparib is most preferably 20-40 wt%, the matrix polymers are preferably 50-80 wt%, and the other additives (surfactants, lubricants) are preferably 0-10 wt% (pages 5-6, paragraphs [0021-0023 and 0028]; page 24, claim 4). This corresponds to an Olaparib:Total Matrix Polymer ratio of 1:1.25 – 1:4. Gan further teaches both the controlled/sustained release and immediate release formulations of the pharmaceutical composition can be in tablet form (page 6, paragraphs [0030-0033]; page 25, claim 5).
MPEP § 2144.05 states:
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, 191 USPQ 90 (CCPA 1976); In re Woodruff, 919 F.2d 1575, 16 USPQ2d 1934 (Fed. Cir. 1990). Even a slight overlap in range establishes a prima facie case of obviousness. In re Peterson, 65 USPQ2d 1379, 1382 (Fed. Cir. 2003).
Gan does not teach the particular weight ratios recited between carrier materials, or the use of polyethylene glycol 1000 vitamin E succinate (TPGS) as the solubilizer.
Huang teaches the use of d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) as a surfactant used to aid in solubilizing the poorly water-soluble API in a solid dispersion, using a hot melt extrusion technique (pages 5-6, paragraphs [0047] and [0054]).
It would have been prima facie obvious to a person of ordinary skill in the art to substitute the surfactants claimed by Gan with the d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) of Huang. This substitution would be motivated by the potential for further improved dissolution properties, and increased bioavailability of Olaparib in a solid dispersion. Furthermore, it is common knowledge in the art that d-α-Tocopheryl polyethylene glycol 1000 succinate (vitamin E TPGS) is primarily used as a solubilizer in pharmaceutical formulations because of its surfactant properties.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Moreover, it would have been prima facie obvious to one of ordinary skill in the art to utilize the amounts of matrix polymer solubilizer (carrier) taught by Gan in claim 4 as a starting point for optimizing the drug delivery rate of Olaparib utilized to treat cancer, since Gan teaches Olaparib is useful for treating cancer, and because the “release rate adjusting” (page 5, paragraph [0026]; page 24, claim 4, line 25) matrix polymer solubilizer ratio is a result-effective variable, i.e. a variable that achieves a recognized result. Therefore, the determination of the optimum matrix polymer solubilizer ratio would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the compositions and the criticality of the claimed dosage range, the determination of the optimum matrix polymer solubilizer ratio given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. Please see MPEP 2144.05(II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation.").
Regarding claims 3, 5-6 and 14-15, Gan and Huang render the pharmaceutical composition of claim 1 obvious as discussed in the above rejection. It is noted that: "[W]here 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." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955).
Taken together, all of this would result in the pharmaceutical composition of instant claims 1, 3, 5-7, 10-11, 14-15 and 19 with a reasonable expectation of success.
Claims 1, 10, 12 and 20 are rejected under 35 U.S.C. 103 as being unpatentable over Gan et al (EP 3556369 A1), cited in a previous Office action; in view of Huang et al (US 2015/0182457 A1), cited in a previous Office action as applied to claims 1, 3, 5-7, 10-11, 14-15 and 19 above; and further in view of Robson et al (The New England Journal of Medicine, 377(6), 523-533), cited in a previous Office action.
Regarding claims 1, 10, 12 and 20, Gan and Huang render the pharmaceutical composition of claim 1 in tablet form obvious as discussed in the above rejection. Gan teaches the use of the Olaparib composition for preparing a medicament for treating tumors related to BRCA gene mutation, such as ovarian, gastric and breast cancer in tablet form (pages 25-26, claims 9 and 10)
Gan does not teach a method of treating a tumor comprising administering the pharmaceutical formulation to a subject.
Robson teaches the administration of Olaparib as a monotherapy to patients with breast cancer. “Olaparib monotherapy was compared with standard therapy in patients with a germline BRCA mutation and human epidermal growth factor receptor type 2 (HER2)–negative metastatic breast cancer”; patients were administered 300mg Olaparib tablets twice per day (page 523, second paragraph). Robson further teaches, “Among patients with HER2-negative metastatic breast cancer and a germline BRCA mutation, Olaparib monotherapy provided a significant benefit over standard therapy; median progression-free survival was 2.8 months longer and the risk of disease progression or death was 42% lower with Olaparib monotherapy than with standard therapy” (page 523, last paragraph).
It would be prima facie obvious to a person of ordinary skill in the art to apply the solubility enhancing compositions and methods of Gan and Huang to the known method of Olaparib tablet administration to patients in need thereof to treat breast cancer in Robson, motivated by the increased and more consistent bioavailability; and improved therapeutic outcomes of a composition with improved dissolution properties.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art.” KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Taken together, all of this would result in the methods of instant claims 1, 10, 12 and 20 with a reasonable expectation of success.
Claim 13 is rejected under 35 U.S.C. 103 as being unpatentable over Gan et al (EP 3556369 A1), cited in a previous Office action; in view of Huang et al (US 2015/0182457 A1), cited in a previous Office action as applied to claims 1, 3, 5-7, 10-11, 14-15 and 19 above; and further in view of Bechtold et al (US 2014/0066447 A1), cited in a previous Office action; further in view of Reynolds (Chemical Engineering Journal, (164)2–3, 2010, 383-392) cited for evidentiary purposes only in a previous Office action.
Regarding claim 13, Gan and Huang render the pharmaceutical composition of claim 1 in tablet form obvious as discussed in the above rejection. Gan teaches a method of manufacturing a solid amorphous dispersion of Olaparib and a matrix polymer via hot melt extrusion as discussed in the above rejection; wherein the final step of processing the extrudate is sieving the extrudate through a 60 mesh screen after the product is pulverized. (page 16, paragraph [0129]; page 24, lines 50-55).
Gan does not teach a cooling step.
Bechtold teaches a method of manufacturing a solid amorphous dispersion of Olaparib, wherein Olaparib and a matrix polymer are mixed and temperatures are increased to melt the mixture and produce a melt. The melt is extruded to produce a solid product. The extrudate is then calandered by passing through two contra-rotating calender rollers (pulverizing), and cooled prior to milling (page 13, paragraph [0154]; page 22, claim 19).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
It would be prima facie obvious to a person of ordinary skill in the art to combine the aforementioned known methods of solid dispersion manufacturing, incorporating Bechtold’s cooling step into the hot-melt extrusion solid dispersion technique of Gan, motivated by the goal of achieving uniform particle size and improved dissolution; an expected, predictable and desirable result.
Furthermore, the process of milling inherently involves sieving as taught by Reynolds, cited for evidentiary purposes only. Reynolds states “Consider the operation of a typical screening mill. Material passes into the mill, which contains a rotating impeller. Within the mill, size reduction of granules occurs by impact attrition with the movement of the impeller forcing sufficiently small material through the screen apertures” (page 384, right column, second paragraph).
The prior art does not explicitly teach the disclosed composition is melted at a temperature range of 120°C-190°C. However, the above chemical and physical parameters depend on, among other things, the specific components, relative amounts, type of formulation, and pH of the formulation etc., all of which seem to be the same or very similar to the composition anticipated, or made obvious by the prior art (see above rejection).
The office does not have the facilities and resources to provide the factual evidence needed in order to establish that the hot melt extruding process that will result from the teachings of the prior art does not possess the same functional characteristics of the specific temperature range of 120°C-190°C claimed in the instant application. In the absence of evidence to the contrary, the burden is on the applicant to prove that the specific temperature range of 120°C-190°C used in the instantly claimed method is different from those taught by the prior art and to establish patentable differences. See In re Best 562F.2d 1252, 195 USPQ 430 (CCPA 1977) and Ex parte Gray 10 USPQ 2d 1922 (PTO Bd. Pat. App. & Int. 1989).
Taken together, all of this would result in the method of instant claim 13 with a reasonable expectation of success.
Applicant argues:
Applicant contends that Gan teaches immediate release Olaparib formulations have limitations such as plasma concentration peaks and valleys, large dosage requirements due to low bioavailability, and inconvenient clinical administration and high costs. Thus, Gan teaches that an immediate release Olaparib formulation is not suitable for clinical treatment. The applicant cites comparative examples of Gan, namely Example 1 of Experimental Example 1, Example 4 of Experimental Example 2 and Example 2 of Experimental Example 3 alleging that Gan teaches immediate release Olaprib formulations are inferior and ultimately is teaching away from immediate release formulations.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
Although Gan does acknowledge the challenges immediate release Olaparib formulations, Gan teaches that immediate release formulations are able to meet the required effective parameter requirements as defined by NDA 3663410 of ≥50% PARP enzyme inhibition level (IC50 value) for ≥13 h, or ≥IC90 value for ≥6 h, with 200mg doses administered twice per day; and ultimately there are not statistically significant differences in therapeutic effects for the two modes of administration, considering the quantitative advantages shown by the experimental results, as AstraZeneca finally chose the dose of 400 mg/2 times/day for new drug application and the marketing of capsule products (pages 2-3, paragraph [00005]). Thus, Gan does NOT teach that immediate release Olaparib compositions are not suitable for clinical treatment, but merely discloses a preference for controlled release formulations.
"[A] reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed." In re DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009).
As shown in the comparative examples, Gan does show that in some instances, controlled release formulations have situational advantages. It is noted that, "A known or obvious composition does not become patentable simply because it has been described as somewhat inferior to some other product for the same use." In re Gurley, 27 F.3d 551, 553, 31 USPQ2d 1130, 1132 (Fed. Cir. 1994).
Furthermore, release rate depends, among other things, from the specific components, relative amounts, type of formulation, and pH of the formulation etc., all of which are the same or substantially similar to the composition made obvious by the prior art (see above rejection). The claims do not recite a limitation requiring a particular release profile. As such, arguments pertaining to comparative release characteristics do not address the specific limitations of the claimed composition. The Applicant has not identified any specific structural or compositional limitation recited in the claims that is absent from the applied prior art.
Applicant argues:
Applicant contends that there is no teaching on the use of copovidone as a suitable second carrier in an immediate dosing formulation as well as a controlled dosing formulation. Applicant states that Gan includes copovidone in a list of multiple carriers that can yield multiple combinations. Applicant states that Gan only teaches carbomer as the second carrier in disclosed multi-carrier formulations, which is differs significantly from copovidone in its intended application and intended effects. Carbomer is directed towards a controlled release dosage form, whereas copovidone is directed towards an immediate release dosage form.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
As noted by the Applicant, Gan includes copovidone as one of a finite list of known suitable carriers, which may be used alone or in combination with other carriers in pharmaceutical formulations. It is well established that the disclosure of specific examples does not limit the broader teaching of a reference.
“Disclosed examples and preferred embodiments do not constitute a teaching away from a broader disclosure or nonpreferred embodiments.” In re Susi, 440 F.2d 442, 169 USPQ 423 (CCPA 1971).
The disclosure of copovidone as one of a limited number of identified carriers evidences that it was recognized in the art as suitable for use in Olaparib compositions. Thus, Gan teaches the use of copovidone in multi-carrier formulations, including as a second carrier, even if not expressly exemplified in a disclosed formulation. The selection of copovidone from this known set of alternatives would have been a routine design choice for one of ordinary skill in the art. Furthermore, the prior art does not require that each listed excipient be used for identical release profiles, but rather reflects that different excipients may be selected depending on the desired formulation characteristics. The selection of a particular carrier, alone or in combination with another particular carrier, to achieve a desired release profile constitutes a routine optimization for someone of ordinary skill in the art.
"[T]he prior art’s mere disclosure of more than one alternative does not constitute a teaching away from any of these alternatives because such disclosure does not criticize, discredit, or otherwise discourage the solution claimed…." In re Fulton, 391 F.3d 1195, 1201, 73 USPQ2d 1141, 1146 (Fed. Cir. 2004).
Thus, the selection of copovidone as the second carrier represents the predictable use of a known carrier for its established function in pharmaceutical formulations, and one of ordinary skill in the art would have had a reasonable expectation of success.
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Applicant argues:
Applicant contends that there is no motivation to combine Huang and Gan because Gan does not teach TPGS, and Huang teaches multiple surfactants but does not mention Olaparib. Applicant further contends that Huang teaches that adding a surfactant can worsen dissolution rates compared to a surfactant free solid dispersion, citing Figs 15 and 17 and the data showing that adding surfactant Span 20 slows the dissolution of a composition comprising ibuprofen, soluplus and eudragrit E, thus providing contradictory guidance.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
It is acknowledged that neither Gan nor Huang explicitly discloses TPGS as the surfactant in a formulation with Olaparib. However as discussed in the above rejection, Gan teaches the use of a surfactant in compositions comprising Olaparib, thereby recognizing the benefit of including a surfactant to improve formulation performance of the poorly water-soluble drug. Huang teaches that TPGS is a surfactant commonly used to aid in solubilizing the poorly water-soluble API in a solid dispersion, using a hot melt extrusion technique (pages 5-6, paragraphs [0047] and [0054]).
MPEP 2144 (I) states:
“The rationale to modify or combine the prior art does not have to be expressly stated in the prior art; the rationale may be expressly or impliedly contained in the prior art or it may be reasoned from knowledge generally available to one of ordinary skill in the art, established scientific principles, or legal precedent established by prior case law. In re Fine, 837 F.2d 1071, 5 USPQ2d 1596 (Fed. Cir. 1988); In re Jones, 958 F.2d 347, 21 USPQ2d 1941 (Fed. Cir. 1992); see also In re Nilssen, 851 F.2d 1401, 1403, 7 USPQ2d 1500, 1502 (Fed. Cir. 1988) (references do not have to explicitly suggest combining teachings).”
Applicant’s argument that Huang teaches away from the use of surfactants is not persuasive. Huang’s disclose that certain surfactants (e.g. Span 20) may reduce dissolution rates in specific formulations is limited to particular compositions and conditions, and does not criticize, discredit or otherwise discourage the general use of surfactants, nor the use of TPGS specifically, for the improving of solubility of poorly water-soluble drugs. To the contrary, Huang explicitly teaches the use of TPGS as a solubilizing surfactant.
"[A] reference does not teach away if it merely expresses a general preference for an alternative invention but does not criticize, discredit or otherwise discourage investigation into the invention claimed." In re DePuy Spine, Inc. v. Medtronic Sofamor Danek, Inc., 567 F.3d 1314, 1327 (Fed. Cir. 2009).
Therefore, the combination of Gan and Huang represents the predictable use of a known surfactant (TPGS) for its established function as a solubilizer in a formulation of a poorly water-soluble drug (Olaparib).
“[T]he rationale to support a conclusion that the claim would have been obvious is that all the claimed elements were known in the prior art and one skilled in the art could have combined the elements as claimed by known methods with no change in their respective functions, and the combination yielded nothing more than predictable results to one of ordinary skill in the art. KSR, 550 U.S. at 416, 82 USPQ2d at 1395.
Applicant argues:
Applicant contends that unexpected technical effects have been achieved by the claimed pharmaceutical composition by improving the solubility, dissolution rate and absorption of Olaparib; further detailing that those skilled in the art would recognize that cyclodextrin features a unique cylindrical cavity capable of encapsulating active ingredients, and is a reversable process attaining a dynamic equilibrium, resulting in a slower dissolution rate of the active ingredient. Thus, one of ordinary skill in the art would not be motivated to include cyclodextrin in the formulation because they would expect it to slow the rate of dissolution of the active ingredient.
Examiner's response:
The above argument has been carefully considered and has not been found persuasive.
It is conceded that Gan does not disclose the unique cylindrical cavity capable of encapsulating active ingredients, but as the applicant has pointed out this was not unknown in the art as evidenced above by Kovvasu, cited for evidentiary purposes only, who teaches that cyclodextrins have long been known to increase the bioavailability, solubility, dissolution rate, chemical stability and absorption of drugs through inclusion complexation via a lipophilic central cavity (page 26, left column, paragraphs 5-7). Thus, one of ordinary skill in the art would expect the use of cyclodextrin to improve the solubility, dissolution rate and absorption of Olaparib and be motivated to include cyclodextrin in the composition.
Conclusion
Claims 1, 3, 5-7, 10-15 and 19-20 are rejected.
No claim is allowed.
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/C.L.J./Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691