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 .
Claim Status
Claims 1-109 and 111 have been cancelled.
Claims 110 and 112-130 are pending. Applicant’s amendment has necessitated modification of the existing rejection. Accordingly, this Action if FINAL.
Withdrawn rejections
Applicant's amendments and arguments filed 1/21/26 are acknowledged and have been fully considered. The Examiner has re-weighed all the evidence of record. Any rejection and/or objection not specifically addressed below is herein withdrawn. Claims 110-130 were rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 10682412 in view of Emanuel (US9173976; hereinafter Emanuel’976) and Puri et al. (WO2010123931) and Sun (WO2018081520). Upon further consideration of Applicant’s amendments to the independent claim and arguments, this rejection is withdrawn.
The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set of rejections and/or objections presently being applied to the instant application.
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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied 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 110 and 112-130 are rejected under 35 U.S.C. 103 as being unpatentable over Emanuel (US20190070298) and Emanuel (US9173976; hereinafter Emanuel’976) and Puri et al. (WO2010123931) and Sun (WO2018081520) and Eckardstein et al. (Journal of Neuro-Oncology 2005;74:305-309).
Applicant claims for example:
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Level of Ordinary Skill in the Art
(MPEP 2141.03)
MPEP 2141.03 (I) states: “The “hypothetical ‘person having ordinary skill in the art’ to which the claimed subject matter pertains would, of necessity have the capability of understanding the scientific and engineering principles applicable to the pertinent art.” Ex parte Hiyamizu, 10 USPQ2d 1393, 1394 (Bd. Pat. App. & Inter. 1988). The level of skill is that of a pharmaceutical cancer research scientist, as is the case here, then one can assume comfortably that such an educated artisan will draw conventional ideas from cancer medicine, cancer therapeutic formulation and administration, pharmacy, physiology and chemistry— without being told to do so.
In addition, the prior art itself reflects an appropriate level (MPEP 2141.03(II)).
Determination of the scope and content of the prior art
(MPEP 2141.01)
Regarding claims 110, 115-118, 120, 124 and 128, Emanuel teaches tri-calcium phosphate (TCP) particles coated with a matrix system, hence shaped in the form of particles, comprising:
a pharmaceutical active agent docetaxel, which is a taxane and reads on component (c) (Claims 75 and 82);
a biodegradable polyester such as PLA or PGA or PLGA (Claims 75 and 77), which reads on component (b);
a lipid comprising a sterol such as cholesterol (Claims 75 and 92);
a second lipid comprising at least one phospholipid having hydrocarbon chains of at least 14 carbons such as phosphatidylcholine (Claims 75 and 76) or 1,2-dimyristoyl-sn-glycero-3-phosphocholine (DMPC), 1,2-dipalmitoyl-sn-glycero-3-phosphocholine (DPPC), 1,2-distearoyl-sn-glycero-3-phosphocholine (DSPC), 1,2-dioleoylsn-glycero-3-phosphocholine (DOPC) and any combination thereof (Claim 94), which reads on component (a) and renders obvious phospholipids having a carbon chain of at least 12 carbons. Emanuel teaches that the composition “further comprises cholesterol” [0027], which means embodiments exist without any cholesterol, and Emanuel teaches an embodiment with 10% cholesterol [0052, 0059, 0065, 0305]. Thus, a range of 0-10% is established. It is the Examiner’s position that the coating process naturally impregnates any pores in the TCP.
Regarding claims 125-126, Emanuel teaches adding a buffer agent [0164, 0210] and a physiological pH of between 6-8, which touches the claimed range of between 4 and 6.
Further regarding claim 115, Emanuel renders obvious employing either docetaxel or doxycycline as the active agent (Claims 80 and 82) and suggests other taxanes such as paclitaxel [0139], which then renders obvious other taxanes such as cabazitaxel to the ordinary artisan in this art.
Regarding claims 110, 117-121 and 128, Emanuel’976 teaches compositions comprising:
About 80-90% w/w coated β-TCP particles with an average size of 1.0mm or less (Column 5, lines 55-64; claims 1, 4), where 1.0 mm or less overlaps the claimed range of less than about 200 microns or 90-95% β-TCP (Claim 8);
0.4-0.6 % cholesterol (Claim 8), which lies within the 0-2% claimed;
1.0-2.0 % PLGA (Claim 8), which overlaps the claimed range of 0.5-5% and 1-4%;
2.0-4.0% of DPPC and 0.7-1.3% of DSPC (Claim 8), thus providing a combined phospholipid range of 2.7-5.3% which overlaps the claimed range of 4.0-15%; and
0.4-2% doxycycline (Claims 7-8), which lies within the amount of active agent claimed in claim 128.
See also claims 10-11. Emanuel’976 teaches DMPC, DPPC or DSPC as functional equivalents that differ by 2 and 4 carbons in the acyl chains (Column 18, lines 15-17).
Regarding claims 110, 112-113, 115, 116 and 128, Puri et al. teach methods of treating solid tumors (Title; Abstract) with a therapeutically effective amount of taxanes such as paclitaxel and docetaxel (Claims 21 and 22), where the solid tumor is selected from the group consisting of pancreatic cancer; bladder cancer; colorectal cancer; breast cancer, including metastatic breast cancer; prostate cancer, including androgen-dependent and androgen-independent prostate cancer; renal cancer, including, e.g., metastatic renal cell carcinoma; hepatocellular cancer; lung cancer, including, e.g., non-small cell lung cancer (NSCLC), bronchioloalveolar carcinoma (BAC), and adenocarcinoma of the lung; ovarian cancer, including, e.g., progressive epithelial or primary peritoneal cancer; cervical cancer; gastric cancer; esophageal cancer; head and neck cancer, including, e.g., squamous cell carcinoma of the head and neck; melanoma; neuroendocrine cancer, including metastatic neuroendocrine tumors; brain tumors, including, e.g., glioma, anaplastic oligodendroglioma, adult glioblastoma multiforme, and adult anaplastic astrocytoma; bone cancer; and soft tissue sarcoma ([0096]; claims 3-4 and 9). The glioblastoma multiforme is a primary brain tumor and the disclosure of other metastatic cancer renders obvious metastatic brain tumors.
Regarding claim 130, Puri et al. teach pharmaceutical compositions such as dispersions/suspensions for injection [00107] that can comprise phosphatidylcholines both natural and synthetic [00108] or even as powders [00109] or pastes [00119].
Regarding claims 125-126, Sun teaches docetaxel formulations with a pH of about 5-8 (Abstract) or about 4-6 in aqueous saline with buffering agents (Page 39, lines 23-31).
Regarding claim 110, Eckardstein et al. teach a single local administration of a paclitaxel composition to a resected solid brain tumor (Summary and Page 306 right column: “Patients underwent microsurgical removal of the tumor with the attempt to resect as much tumor tissue as regarded possible and safe by the surgeon. Specimens were sent to pathology. After completing tumor removal the resection zone was covered with the cytotoxic carrier system.”)
Ascertainment of the difference between the prior art and the claims
(MPEP 2141.02) and Finding of prima facie obviousness
Rational and Motivation (MPEP 2142-2143)
First, the Examiner will show that the claimed pharmaceutical composition is obvious over the combined references of Emanuel and Emanuel’976 and Sun. Secondly, the Examiner will show that pharmaceutical composition of Emanuel as modified by Emanuel’976 and Sun is obvious to be used in methods of treating a solid tumor by the teachings of Puri et al. and Eckardstein et al.
1. The difference between the instant application and Emanuel is that Emanuel do not expressly teach the amount of each component in the composition or particle size of β-TCP or the pH is between 4 and 6. This deficiency in Emanuel is cured by the teachings of Emanuel’976 and Sun.
1. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to optimize the amount of each component and employ a β-TCP particle size of less than about 200 microns, as suggested by Emanuel’976, and adjust the pH to between 4 and 6, as taught by Sun, and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Emanuel’976 appears to teach the same β-TCP based compositions but with guidance on how much of each component to employ and to use particles of β-TCP that are less than 1000 microns in size which overlaps the claimed range of less than about 200 microns. See 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, 191 USPQ 90 (CCPA 1976). The ordinary artisan with the references in hand and without any undue experimentation would readily derive the docetaxel bearing β-TCP particles of Emanuel with the teachings of Emanuel’976 to obtain:
80% - 93% (w/w) of β-tricalcium phosphate particles;
1%-4% (w/w) of PLGA;
4% - 15% (w/w) DMPC;
0% - 2% (w/w) of cholesterol; and
0.2% to 2.6% or about 0.5 to 1.5% (w/w) of docetaxel;
with a reasonable expectation of success. See MPEP 2144.05 (II) (A): “[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). Especially when DMPC is taught to be a functional equivalent. “Where two known alternatives are interchangeable for a desired function, an express suggestion to substitute one for the other is not needed to render a substitution obvious." In re Fout 675 F.2d 297, 301 (CCPA 1982). Consequently, the claimed pharmaceutical composition components in the amounts claimed is obvious over the combined references.
With regard to the pH, as noted above Emanuel does teach and suggest adding a buffer agent, which is a pH adjustment agent, and Sun teaches pH ranges between 4 and 6 for docetaxel aqueous formulations. Thus, the ordinary artisan would have a reasonable expectation of success in formulating an aqueous pharmaceutical formulation with a pH between 4 and 6 with pH adjusting agents in the absence of evidence to the contrary.
2. The difference between the instant application and Emanuel as modified by Emaneul’976 and Sun is that Emanuel as modified by Emaneul’976 and Sun do not expressly teach administration for treating the named solid tumors and applied to the inner surface of a resection cavity of the solid tumor at a dose ranging from 20 mg to 260 mg per surface area of 1 cm2 and where the solid tumor is docetaxel resistant tumor and wherein the taxane penetrates to a distance of at least 1 cm away from the surface of the solid tumor, wherein the solid tumor has been resected and wherein the pharmaceutical composition is for a single local administration. This deficiency in Emanuel as modified by Emaneul’976 and Sun is cured by the teachings of Puri et al. and Eckardstein et al.
2. It would have been obvious to one of ordinary skill in the art prior to the effective filing date of the claimed invention to employ the composition of Emanuel as modified by Emaneul’976 and Sun in methods of treating a solid tumor by administering to a subject the composition to treat the solid tumors claimed, as suggested by Puri et al., and applied to the inner surface of a resection cavity of the solid tumor at a dose ranging from 20 mg to 260 mg per surface area of 1 cm2 and where the solid tumor is docetaxel resistant tumor and wherein the taxane penetrates to a distance of at least 1 cm away from the surface of the solid tumor, wherein the solid tumor has been resected and wherein the pharmaceutical composition is for a single local administration, as suggested by Eckardstein et al., and produce the instant invention.
One of ordinary skill in the art would have been motivated to do this because Emanuel teaches employing the anticancer agent docetaxel in the composition for treating cancer tumor [0138] and Puri et al. teach the claimed solid tumors that can be treated with docetaxel. It is then obvious to administer the composition of Emanuel as modified by Emanuel’976 and Sun to treat any of the claimed solid tumors with a reasonable expectation of success. Application of to the inner surface of a resection cavity of the solid tumor at a dose ranging from 20 mg to 260 mg per surface area of 1 cm2 is at the discretion and optimization of the artisan performing the treatment on the patient in order to administer a therapeutically effective amount to treat the respective tumor. Resection and identification of the tumor as a treatment resistant tumor is also within the skill of the ordinary artisan. Emanuel teaches administration after one or more additional treatments such as surgical removal of the tumor as well [0138], which is surgical tumor resection. A single local administration of the composition to the resected cavity is rendered obvious through the teaches of Eckardstein et al. Additionally, the ordinary artisan in this art would be well aware of such intracavitary chemotherapy as a therapy in their toolkit of parenteral treatment routes of administration. The limitation of wherein the taxane penetrates to a distance of at least 1 cm away from the surface of the solid tumor, wherein the solid tumor has been resected is an implicit property of the TCP particles of Emanuel as modified by Emanuel’976, Sun and Eckardstein et al.
In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103.
From the combined teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the combined references, especially in the absence of evidence to the contrary.
Response to Arguments:
Applicant’s arguments filed on 1/21/26 have been carefully considered but are not persuasive.
With regard to Emanuel and Emanuel’976, Applicant asserts that: “there is no disclosure whatsoever of brain-related indications, let alone solid brain tumors.” However, those references are not relied upon for teaching a solid brain tumor and the rejection is over a combination of references. Puri is relied upon for that teaching. It is impermissible to attack references singly when the Examiner relies upon the combined teachings of the references, nor may they attack a reference for not teaching a limitation of the claim when the Examiner has explicitly relied upon another reference as teaching that limitation. See In re Kotzab, 217 F.3d 1365, 1370 (Fed. Cir. 2000). Applicant’s arguments are not persuasive.
With regard to Puri, Applicant asserts that: “there is no guidance or teaching that suggests Compound I can treat solid brain tumors. Puri does not describe, suggest, or contemplate a delivery system for sustained release of a chemotherapeutic drug for treating a solid brain tumor… Puri fails to describe administration or local administration to a resection cavity of a solid brain tumor.” Respectfully, the Examiner has a different perspective as Puri teaches that types of tumors treatable with taxanes such as paclitaxel and docetaxel. Puri is not relied upon for the delivery system or local administration to a resection cavity of a solid brain tumor. Applicant’s arguments are not persuasive.
With regard to Sun, Applicant argues that: “there is nothing in Sun that teaches its complex of docetaxel and HSA can treat solid brain tumors.” However, Sun is not relied upon for that teaching. The test for obviousness is "what the combined teachings of the references would have suggested to those of ordinary skill in the art." In re Keller, 642 F.2d 4I3, 425 (CCPA I98I) (MPEP 2145(III)). In the present case, the combined references render obvious each and every claimed limitation. At this time, no evidence of unexpected results has been presented or argued. Consequently, the claimed method is obvious in view of the combined references.
On page 8 of remarks, Applicant asserts: “The present Application provides a solution by a single administration of a taxane molecule in a sustained release manner immediately after the surgical removal of the tumor, enabling the presence of the taxane molecule, at the tumor site immediately after surgery. None of the cited references provide such solution.” However, single local administration of a taxane to a resected tumor cavity, intracavitary chemotherapy, has been known since at least 2005 (Eckardstein et al.) This is a known administration route the ordinary artisan in this art can employ with a reasonable expectation of success.
MPEP 2141 III states: “The proper analysis is whether the claimed invention would have been obvious to one of ordinary skill in the art after consideration of all the facts.” Respectfully, after review of all the facts, Applicant’s arguments are not persuasive. The Examiner has reached a determination that the instant claims are not patentable in view of the preponderance of evidence and consideration of all the facts, which is more convincing than the evidence which has been offered in opposition to it.
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.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ERNST V ARNOLD whose telephone number is (571)272-8509. The examiner can normally be reached M-F 7-3:30.
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/ERNST V ARNOLD/Primary Examiner, Art Unit 1613