DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Sequence Compliance
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 CFR 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 CFR 1.821 through 1.825 because there is a sequence on page 7 of the specification that do not contain a SEQ ID NO.
37 CFR 1.821 Nucleotide and/or amino acid sequence disclosures in patent applications.
(a) Nucleotide and/or amino acid sequences, as used in §§ 1.821 through 1.825, are interpreted to mean an unbranched sequence of 4 or more amino acids or an unbranched sequence of 10 or more nucleotides. Branched sequences are specifically excluded from this definition. Sequences with fewer than four specifically defined nucleotides or amino acids are specifically excluded from this section.
A complete response to this office action must correct the defects cited above regarding compliance with the sequence rules and a response to the action on the merits which follows.
The aforementioned instance of failure to comply is not intended as an exhaustive list of all such potential failures to comply in the instant application. Applicants are encouraged to thoroughly review the application to ensure that the entire application is in full compliance with all sequence rules. This requirement will not be held in abeyance.
Claim Rejections - 35 USC § 102
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 the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1 and 5-18 is/are rejected under 35 U.S.C. (a)(2) as being anticipated by Katz et al. (WO 2022/212690 A1).
Katz et al. teach a method of treating HCC via hepatic arterial infusion [0010] via delivery of instant SEQ ID NO: 1 (claim 1) (instant claim 1).
Katz et al. teach: [0013] In some embodiments, the amount of TLR agonist administered is in the range of about 0.01-20 mg, or at least one of 0.5 mg, 2 mg, 4 mg, or 8 mg (instant claim 6).
Katz et al. teach: [0015] In some embodiments, the TLR agonist is administered in the range of .0001-20 mg/mL, or at least one of .01 mg/mL, .04 mg/mL, .08 mg/mL, or .16 mg/mL (instant claim 5).
Katz et al. teach: [0016] In some embodiments, the TLR agonist is administered for a period of time of about 10-200 minutes. In another embodiment, the TLR agonist is administered for a period of time of about 10-60 minutes. In another embodiment, the TLR agonist is administered for a period of time of about 25 minutes (instant claims 10-12).
Katz et al. teach: 0017] In some embodiments, the TLR agonist is administered in combination with one or more CPIs. In some embodiments, the CPIs are administered systemically, either concurrently, before, or after the administration of the TLR agonist. In some embodiments, the CPIs include at least one of nivolumab, pembrolizumab, and ipilimumab (instant claims 13, 14, and 18).
Katz et al. teach: [0018] In some embodiments, administration of the TLR agonist comprises a dosing regimen comprising cycles. In some embodiments, one or more of the cycles comprise the administration of the TLR agonist via a catheter device by HAI followed by the systemic administration of one or more CPIs (instant claims 7 and 15).
Katz et al. teach: [0019] In some embodiments, one cycle of the dosing regimen comprises the administration of the TLR agonist once per week over three consecutive weeks. In some embodiments, the dosing regimen comprises two cycles (instant claims 16 and 17).
Katz et al. teach: [0083] The TriNav.sup.® is a single lumen catheter equipped with a one-way valve that responds dynamically to local and flow changes (instant claim 8).
Katz et al. teach: [0086] According to an embodiment, the toll-like receptor agonist or agonists are introduced through the percutaneous introduction of a device into the branches of a hepatic artery or portal vein, such as a catheter and/or a device that facilitates pressure-enabled delivery (instant claim 9).
Therefore, the claims are anticipated by Katz et al.
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.
Claim(s) 1 and 5-18 is/are rejected under 35 U.S.C. 103 as being unpatentable over Krieg (US 10,682,365 B2), in view of Morris et al. (J Immunother Cancer 2020;8(Suppl 3):A360-A361), Anand et al. (US 2019/0160254 A1), Carpentier et al. (Neuro-Oncology 12(4):401–408, 2010), and Nishikawa et al. (Cancers 2012, 4, 165-183).
Krieg teaches that the CpG ODN can bind and stimulate TLR9 (column 3) and that the ODN sequence is 100% identical to instant SEQ ID NO: 1 (Table 2, last sequence, CpG-A oligo).
Krieg teaches that the cancer can be hepatocellular carcinoma or cholangiocarcinoma (columns 74 and 77) (instant claim 1).
Morris et al. is additional evidence that it was known to deliver a TLR9 agonist to treat hepatocellular carcinoma.
Krieg does not teach that the TLR9 agonist is administered through a device by hepatic arterial infusion. Krieg does not teach administration through a catheter (instant claim 7) that comprises a one-way valve that responds dynamically to local pressure and/or flow changes (instant claim 8) or via pressure-enabled drug delivery via the catheter (instant claim 9).
However, Krieg does teach administration via infusion (column 89) and teaches:
vehicles or delivery devices for delivering oligonucleotides and/or antigens to surfaces have been described. The CpG ODN and/or the antigen and/or other therapeutics may be administered alone (e.g., in saline or buffer) or using any delivery vehicles known in the art (column 95).
It was known in the art that oligonucleotides can be delivered via a catheter with a one-way valve to control the direction of fluid flow, as taught by Anand et al. ([0011][0013][0180]); wherein the delivery is via pressure-enabled drug delivery [0009]. The valve responds to pressure/flow [0192]. It would have been obvious to deliver the oligomer of Krieg via the catheter of Anand with a reasonable expectation of controlled delivery of the drug, a benefit taught by Anand (instant claims 7-9).
Anand et al. teach: For example, the systems and methods disclosed herein can be used for intraarterial or intravenous delivery. Such systems and methods can include infusion and/or aspiration that is coordinated with one or more physiological parameters of a patient (e.g., natural CSF flow, heart rate, respiration rate, etc.) [0224]. When targeting hepatocellular carcinoma, it would have been obvious to utilize the delivery systems of Anand et al. for hepatic arterial or portal vein infusion in a controlled manner as a matter of design choice given that it was known to be a successful delivery device for oligomers (instant claim 1).
Krieg does not teach administration for 10-100, 10-60, or for about 25 minutes (instant claims 10-12); or once per week over three consecutive weeks (instant claim 16). However, Krieg teaches: Administration of these therapeutic agents in combination typically is carried out over a defined time period (usually minutes, hours, days, or weeks depending upon the combination selected) (column 18); and teaches that: the skilled artisan would appreciate, based upon the disclosure provided herein, that the dose and dosing regimen is adjusted in accordance with methods well-known in the therapeutic arts. That is, the maximum tolerable dose can be readily established, and the effective amount providing a detectable therapeutic benefit to a patient can also be determined, as can the temporal requirements for administering each agent to provide a detectable therapeutic benefit to the patient. Accordingly, while certain dose and administration regimens are exemplified herein, these examples in no way limit the dose and administration regimen that can be provided to a patient in practicing the present invention. Further, one skilled in the art would understand, once armed with the teachings provided herein, that a therapeutic benefit, such as, but not limited to, detectable decrease in tumor size and/or metastasis, and increased time to recurrence, among many other parameters, can be assessed by a wide variety of methods known in the art for assessing the efficacy of treatment of cancer, and these methods are encompassed herein, as well as methods to be developed in the future (columns 87 and 88).
Krieg teach that the subject doses of CpG ODN for intratumoral and peritumoral delivery typically range from about 10ug to about 100 mg per administration and could be given daily, weekly, or monthly and any time therebetween; or 1-50 mg per dose (column 90); or 1mg-10mg per dose (column 91) (instant claims 5 and 6).
Therefore, administration of the instantly dosage schedules is considered to be a matter of design choice and well within the technical grasp of one of ordinary skill in the art. Krieg teaches that administration is carried out over minutes and teaches that the parameters are routinely established (instant claims 5, 6, 10-12, 16, and 17).
Krieg teaches: Provided are methods for treating cancer using local administration of certain CpG oligonucleotides (CpG ODN) and systemic administration of a checkpoint inhibitor such as an anti-PD-1 antibody, an anti-PD-L1 antibody, and/or an anti-CTLA-4 antibody (abstract) (instant claims 13 and 15).
Krieg teaches that the anti-PD-1 antibody can be nivolumab, pembrolizumab (column 68), or ipiliumumab (column 70)(instant claims 14 and 18).
Carpentier et al. is additional evidence that it was known to deliver CpG-ODN via catheters implanted in the tumor mass in patients. The primary objective was efficacy, based on PFS. Secondary outcomes were tolerance, survival, and radiological response (page 402). Therefore, this would have been an obvious method to deliver the oligomer of Krieg with a reasonable expectation of success (instant claims 7-9).
Additionally, it was known to treat HCC via hepatic arterial infusion of a drug, as evidenced by Nishikawa et al. Therefore, it would have been an obvious means to select to deliver the oligomer of Krieg.
Nishikawa et al. teach: Transcatheter methods such as transcatheter arterial chemoembolization (TACE) and hepatic arterial infusion chemotherapy (HAIC) have an important role in the treatment for advanced hepatocellular carcinoma (HCC) (abstract).
Nishikawa et al. teach: There are several case reports showing a favorable response of advanced HCC to combination therapy with sorafenib and HAIC (page 173).
Response to Arguments
Applicant argues that the HAI administration of the TLR9 agonist of SEQ ID NO. 1 (SD-101) is shown in the Specification of the present application to provide unexpected benefit of improved distribution in and around the tumor with low drug exposure in normal liver tissue. It is noted that the instant claims are not limited to the device argued by applicant and therefore applicant is arguing limitations that are not claimed. Additionally, HAI would have been expected to result in controlled delivery of the oligomer, as taught by Anand et al. It was known to utilize a catheter with a valve that responds to pressure/flow, as taught by Ananad et al. and it would have been obvious to deliver the oligomer of Krieg via the catheter of Anand with a reasonable expectation of controlled delivery of the drug, a benefit taught by Anand.
Anand et al. teach: For example, the systems and methods disclosed herein can be used for intraarterial or intravenous delivery. Such systems and methods can include infusion and/or aspiration that is coordinated with one or more physiological parameters of a patient (e.g., natural CSF flow, heart rate, respiration rate, etc.) [0224]. Therefore, one would have expected for the device of Anand et al. to result in benefits of controlled delivery of the oligomer of Krieg. It is not unexpected for HAI to have resulted in delivery to the tumor and the motivation in the art does not need to be identical to that of applicant. Krieg teaches that delivery is customized to the patients needs and specific therapeutic application. Exemplary parameters that can be controlled by the controller include infusion type, infusion rate, infusion volume, time between infusions, oscillatory rate, infusion and withdraw ratio, infusion phase timing, aspiration type, aspiration rate, time between aspirations, aspiration volume, and so forth [0198]. When controlling these parameters, certainly one would expect for the device to deliver the agent to the target successfully.
Anand et al. teach: [0201] As noted above, one or more components of the delivery system and, in some embodiments, all components of the delivery system, can be implanted in the patient. Implanting some or all of the delivery system can facilitate chronic or long-term drug delivery (e.g., over a period of days, weeks, months, or years) via non-invasive or outpatient procedures.
Anand et al. specifically teach that the device can achieve localized delivery with substantially instantaneous distribution [0207]. [0212] The systems disclosed herein can be used in any of a variety of drug delivery methods.
Applicant argues that Example 1 of the present application shows that "pressure-enabled delivery of labeled SD-101 using a TriNav® resulted in the preferential accumulation of fluorescent compound in the region around the actively growing primary liver tumor periphery and surrounding normal tissue, in which the region is expected to contain the bulk of immune cells expressing TLR9, which is the target of SD-101. However, delivery to the tumor with the device of Anand et al. would be expected to result in delivery to the same area argued by applicant. The instant method is directed to a method of treating HCC via delivery of instant SEQ ID NO: 1 via any device for HAI, a method that is obvious in view of the cited references. The results argued by applicant are not commensurate in scope with the claims language.
Additionally, it was known to treat HCC specifically via hepatic arterial infusion of a drug, as evidenced by Nishikawa et al. Therefore, it would have been an obvious means to select to deliver the oligomer of Krieg with a reasonable expectation of the benefits of HAI as taught by Nishikawa et al.
Applicant argues that Lee et al. ( J Clin. Oncol., 42 (16_suppl): 2622) demonstrates instant Example 2 (which is prophetic in the specification) and demonstrates the unexpected benefits of hepatic arterial infusion (HAI) of SD-101 (the TLR agonist of SEQ ID NO: 1) with pressure-enabled drug delivery (PEDD) to enhance immunotherapy (ICI) responsiveness in intrahepatic cholangiocarcinoma and hepatocellular carcinoma. Lee et al. teach HAI of SD-101 via the TriNav device (which is not commensurate in scope with the instant claims) with resultant treatment effect in HCC. This is not demonstrative of an unexpected result because HAI of SEQ ID NO: 1 is expected to have the benefits of Nishikawa et al. and Anand et al. and it was clearly obvious to deliver the oligomer to the hepatic artery to treat HCC.
Double Patenting
The nonstatutory double patenting rejection is based on a judicially created doctrine grounded in public policy (a policy reflected in the statute) so as to prevent the unjustified or improper timewise extension of the “right to exclude” granted by a patent and to prevent possible harassment by multiple assignees. A nonstatutory double patenting rejection is appropriate where the conflicting claims are not identical, but at least one examined application claim is not patentably distinct from the reference claim(s) because the examined application claim is either anticipated by, or would have been obvious over, the reference claim(s). See, e.g., In re Berg, 140 F.3d 1428, 46 USPQ2d 1226 (Fed. Cir. 1998); In re Goodman, 11 F.3d 1046, 29 USPQ2d 2010 (Fed. Cir. 1993); In re Longi, 759 F.2d 887, 225 USPQ 645 (Fed. Cir. 1985); In re Van Ornum, 686 F.2d 937, 214 USPQ 761 (CCPA 1982); In re Vogel, 422 F.2d 438, 164 USPQ 619 (CCPA 1970); In re Thorington, 418 F.2d 528, 163 USPQ 644 (CCPA 1969).
A timely filed terminal disclaimer in compliance with 37 CFR 1.321(c) or 1.321(d) may be used to overcome an actual or provisional rejection based on nonstatutory double patenting provided the reference application or patent either is shown to be commonly owned with the examined application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. See MPEP § 717.02 for applications subject to examination under the first inventor to file provisions of the AIA as explained in MPEP § 2159. See MPEP § 2146 et seq. for applications not subject to examination under the first inventor to file provisions of the AIA . A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The filing of a terminal disclaimer by itself is not a complete reply to a nonstatutory double patenting (NSDP) rejection. A complete reply requires that the terminal disclaimer be accompanied by a reply requesting reconsideration of the prior Office action. Even where the NSDP rejection is provisional the reply must be complete. See MPEP § 804, subsection I.B.1. For a reply to a non-final Office action, see 37 CFR 1.111(a). For a reply to final Office action, see 37 CFR 1.113(c). A request for reconsideration while not provided for in 37 CFR 1.113(c) may be filed after final for consideration. See MPEP §§ 706.07(e) and 714.13.
The USPTO Internet website contains terminal disclaimer forms which may be used. Please visit www.uspto.gov/patent/patents-forms. The actual filing date of the application in which the form is filed determines what form (e.g., PTO/SB/25, PTO/SB/26, PTO/AIA /25, or PTO/AIA /26) should be used. A web-based eTerminal Disclaimer may be filled out completely online using web-screens. An eTerminal Disclaimer that meets all requirements is auto-processed and approved immediately upon submission. For more information about eTerminal Disclaimers, refer to www.uspto.gov/patents/apply/applying-online/eterminal-disclaimer.
Claims 1 and 5-18 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-11 and 15-18 of copending Application No. 18/730,982 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the claims of application ‘982 are directed to: a method for treating liver immune dysfunction comprising administering to a subject in need thereof a therapeutically effective amount of a toll-like receptor 9 agonist having the structure: 5'-TCG AAC GTT CGA ACG TTC GAA CGT TCG AAT-3' (SEQ ID NO: 1), wherein the liver immune dysfunction is induced by at least one tumor resulting from metastasis in the liver or at least one primary liver cancer (claim 1). Therefore, application ‘982 is directed to treating a patient that has a primary liver cancer with the same oligomer as instantly recited (instant claim 1). Additionally, primary liver cancer can be considered to be a liver immune dysfunction due to its ability to evade the immune system. The claims are directed to the same modes of administration/delivery devices, dosing, and checkpoint inhibitors. The claims are obvious variations of each other.
The remainder of the claims of application ‘982 and correlation to the instant claims are as follows:
2. (Original) The method of claim 1, wherein the TLR9 agonist is administered through a device by hepatic arterial infusion (HAI) (instant claim 3).
3. (Original) The method of claim 1, wherein the TLR9 agonist is administered through a device by portal vein infusion (PVI) (instant claim 4).
4. (Original) The method of claim 1, wherein the therapeutically effective amount of the TLR9 agonist administered is in the range of about 0.01-20 mg (instant claims 5 and 6).
5. (Original) The method of claim 4, wherein the therapeutically effective amount of the TLR9 agonist administered is selected from the group consisting of 2 mg, 4 mg, or 8 mg (instant claim 6).
6. (Currently Amended) The method of claim 1, wherein the TLR9 agonist may be administered through a catheter device (instant claim 7).
7. (Original) The method of claim 6, wherein the catheter device comprises a one-way valve that responds dynamically to local pressure and/or flow changes (instant claim 8).
8. (Original) The method of claim 6, wherein the TLR9 agonist is administered through the catheter device via pressure-enabled drug delivery (instant claim 9).
9. (Original) The method of claim 6, wherein the TLR9 agonist is administered for a period of time of about 10-200 minutes (instant claim 10).
10. (Original) The method of claim 9, wherein the TLR9 agonist is administered for a period of time of about 10-60 minutes (instant claim 11).
11. (Original) The method of claim 10, wherein the TLR9 agonist is administered for a period of time of about 25 minutes (instant claim 12).
15. (Currently Amended) The method of claim 1, wherein the TLR9 agonist is administered in combination with one or more checkpoint inhibitors (instant claim 13).
16. (Original) The method of claim 15, wherein the checkpoint inhibitors are administered systemically, either concurrently, before, or after the administration of the TLR9 agonist (instant claim 13).
17. (Original) The method of claim 16, wherein the one or more checkpoint inhibitors include at least one of nivolumab, pembrolizumab, and ipilimumab (instant claims 14 and 18).
18. (Original) The method of claim 16, wherein the administration of the TLR9 agonist comprises a dosing regimen comprising cycles, in which one or more of the cycles comprise the administration of the TLR9 agonist via a catheter device by hepatic arterial infusion followed by the systemic administration of the one or more checkpoint inhibitors (instant claims 15-17). The administration once per week for three weeks in an obvious species of dosing regimen that falls within the scope of claim 18.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Terminal Disclaimer
As set forth in the “Terminal Disclaimer review decision” (9/2/26): POA = ATTORNEY IS NOT OF RECORD. The person who signed the Td does not have POA, and is not the applicant, patentee or attorney of record 37 CFR 1.321 (a and b) (only for applications filed on/after 9/16/12), see FP 14.26.08. POA that gives power to the attorney who is signing the TD needs to be filed.
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 Amy R Hudson whose telephone number is (571)272-0755. The examiner can normally be reached M-F 8:00am-6:00pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Neil Hammell can be reached at 571-270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/AMY ROSE HUDSON/Primary Examiner, Art Unit 1636
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