DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application is being examined under the pre-AIA first to invent provisions.
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 3/16/26 has been entered.
Election/Restrictions
Applicant's election with traverse of Group I, claims 3-14, 24, 27-35, 38 and 39, drawn to a method comprising administering antisecretory factor protein for treatment or therapy of glioblastoma in a mammal in the reply filed on July 5, 2023 is acknowledged. The traversal is on the ground(s) that there is no undue search burden for the Examiner. This is not found persuasive because the two inventions have different scope and function. Group I is directed to exogenously administering antisecretory factors to treat GBMs whereas Group II is directed to endogenously administering antisecretory factors to treat GBM1. That is the antisecretory factors comes from different sources. One is within the mammal the other is from some other source outside the mammal.
The requirement is still deemed proper and is therefore made FINAL.
Claims 25, 26, 36 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention there being no allowable generic or linking claim. Applicant timely traversed the restriction (election) requirement in the reply filed on July 5, 2023.
Priority
The instant application, filed 12/28/2021 and having 2 RCE-type filings therein is a Continuation of 14652868 , filed 06/17/2015, now abandoned and having 1 RCE-type filing therein
14652868 is a National Stage entry of PCT/EP2013/077747 , International Filing Date: 12/20/2013, claims foreign priority to 1251473-3, filed 12/20/2012.
Claim Status
The claim listing filed 2/17/26 is pending.
Claim 24-26, 31-34, 36, 37, and 40-46 are pending.
Claims 1-23, 27-30, 35, 38, 39 were canceled.
Claims 25, 26, 36 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention there being no allowable generic or linking claim. Claims 24, 31-34, and 40-46 are under examination.
Claims 24, 31-34, and 40-46 are rejected.
Drawings
Color photographs and color drawings are not accepted in utility applications unless a petition filed under 37 CFR 1.84(a)(2) is granted. Any such petition must be accompanied by the appropriate fee set forth in 37 CFR 1.17(h), one set of color drawings or color photographs, as appropriate, if submitted via the USPTO patent electronic filing system or three sets of color drawings or color photographs, as appropriate, if not submitted via the via USPTO patent electronic filing system, and, unless already present, an amendment to include the following language as the first paragraph of the brief description of the drawings section of the specification:
The patent or application file contains at least one drawing executed in color. As proof of this, see Figure Legends of Figures 1, 3 and 7 of the specification, pages 7 and 8, the examiner noting that the descriptions of Figures 9 and 10 also imply the presence of colors. Copies of this patent or patent application publication with color drawing(s) will be provided by the Office upon request and payment of the necessary fee.
Color photographs will be accepted if the conditions for accepting color drawings and black and white photographs have been satisfied. See 37 CFR 1.84(b)(2).
Specification
The disclosure is objected to because of the following informalities: Figure Legends of Figures 1, 3 and 7 of the specification, pages 7 and 8, refer to colors in the drawings, however such colors are not present in the instant black and white drawings.
Appropriate correction is required.
Claim Objections
Claim 41 is objected to because of the following informalities: for grammatical consistency, in line 2 “is” should be amended to “are”. Appropriate correction is required.
Claim Interpretation - Supplemented
The claim limitations are given their broadest reasonable interpretation (BRI) consistent with the specification, MPEP 2111, and under the BRI, words of the claim must be given their plain meaning, unless such meaning is inconsistent with the specification, MPEP 2111.01.
Regarding claim 24’s “a further pharmaceutical substance” per para 70 of the corresponding
PGPUB No. 20220118047 “is in the present context selected from the group consisting of anticancer drug, antitumor drug, radiation therapy, immunological substances and/or cells and antibiotic substance, a drug targeting posttraumatic injury, a drug targeting neurodegeneration, and a drug against inflammatory conditions.” This is broader than and separate from “formulation comprising an anti-glioblastoma drug” also set forth in claim 24.
The examiner notes that the 2/27/26 claim 24 amendments substantially modify what is being claimed, including that “a pharmaceutical substance” now comprises “an anti-glioblastoma drug”, however the claim substantially differing from previous versions in that the method is “for facilitating and optimizing uptake into glioblastoma cells” of said pharmaceutical substance. In view of such substantial changes and previous final restriction requirement, followed by applicant’s withdrawing of claims, the previous withdrawal of claims is maintained. Further, when considering the statements in the specification regarding optimizing, in paras 149 and 154 of the corresponding PGPUB No. 20220118047, “optimizing” is interpreted broadly to mean “improving,” there being no clear disclosure of an approach or experiment that focuses on and/or attains a particular apogee of cellular uptake of the anti-glioblastoma drug into glioblastoma cells (or of any other representative model).
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 24, 31-34, and 40-46 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
In claim 24, the limitation “a peptide with an amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16)” can be interpreted to mean a) only that specific peptide VCHSKTRSNPENNVGL, or b) any peptide that comprises VCHSKTRSNPENNVGL. One of ordinary skill in the art cannot reasonably determine which meaning to apply given the use of “with an” before “amino acid sequence VCHSKTRSNPENNVGL.” Assuming applicant means to claim a) only that specific peptide, the claim should be amended to “a peptide consisting of the amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16)” or other language that clearly communicates this.
Claims 31-34, and 40-46 are also rejected on this basis as depending from claim 24.
Claim Rejections - 35 USC § 112
The following is a quotation of the first paragraph of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of the first paragraph of pre-AIA 35 U.S.C. 112:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 24, 31-34, and 40-46 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Claim 24 is directed to a method for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment, the method comprising administering to said patient a hexapeptide with an amino acid sequence CHSKTR as shown in SEQ. ID NO: 2 (AF-6), a peptide with an amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16), and/or a pharmaceutically active salt thereof; and thereby facilitating and optimizing uptake into glioblastoma cells of said pharmaceutical substance.
There are neither timing of administrations nor amounts set forth in this or other claims under examination.
Al-Olama et al., Acta Oncologica, 2011; 50: 1098–1104, teaches that the peptide AF-16 induced interstitial fluid pressure (IFP) reduction in solid tumors, and this reduction “was maximal after 90 min, lasted at least 3 h, and returned to pretreatment levels in less than 24 h.,” Abstract.
Assuming that at least part of the “optimizing” effect of AF-16 is related to reduction of IFP, it is reasonable to conclude that administering AF-16 (as well as the other claimed peptide hexamer, which has shorter half-life or stability) at times more than 24 hours from the administering time of the anti-glioblastoma drug would not result in “optimizing” as that term is understood and interpreted. Very likely administering one week, or one month, prior to or after the administering time of the anti-glioblastoma drug would not result in “optimizing”.
Also, there are no amounts required to be administered by one or another route of administering. Any low level of administering a food, such as egg yolk comprising AF-16, which is subject to systemic distribution following digestive degradation, would not reasonably result in “optimizing” as that term is understood and interpreted. There is no evidence or reasonable technical basis provided in the application that systemic administering of AF-16 peptide in food, such as in egg yolks, would afford the optimizing that is claimed for an anti-glioblastoma drug. If evidence exists, applicant may consider providing this toward rebutting this rejection.
Based on the above, applicant is not in possession of the breadth of what is claimed in claim 24. Claims 31-34, and 40-46 are also rejected on this basis as depending from claim 24.
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 pre-AIA 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter 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 pre-AIA 35 U.S.C. 103(a) 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.
Response to Applicant Arguments
Applicant's arguments filed 2/17/26 have been fully considered but they are not persuasive.
Applicant page 5 states that “glioblastoma cells differ in critical respects from other cancer cells; these differences mean that it is almost impossible to get TMZ or any other drug into these cells.”
This is not persuasive because Singh et al., Cancer Drug Resist 2021;4:17-43, clearly teach that TMZ is a prodrug “that is able to cross the blood-brain barrier and can therefore be administered orally. It is stable at acidic pH and is activated at physiological pH through conversion to the metabolite 5-(3-methyltriazen 1-yl) imidazole-4-carboxamide (MTIC). MTIC is then hydrolyzed to produce methyldiazonium ions which are electrophilic methylated molecules that cause DNA damage. Negatively charged DNA acts as a nucleophile and the methyl group from the methyldiazonium ion is transferred to DNA, resulting in multiple DNA adducts that create opportunity for mismatched base pairing and ultimately cytotoxicity,” page 18, citations omitted.
Singh also teaches, “TMZ has become a cornerstone of GBM treatment, but it is unfortunately also a key factor in tumor resistance and recurrence. Due to the widespread exposure to TMZ and highly heterogeneous and mutation prone nature of GBM, it is quite common for these lethal tumors to develop resistance to TMZ. Unfortunately, over 50% of GBM patients treated with TMZ do not respond to the therapy, yet there are limited predictive markers for TMZ response beyond MGMT status. Understanding and combating TMZ resistance is further complicated by the fact that resistance can be either inherently characteristic of certain tumors or acquired after initial treatment,” page 19, citations omitted.
Singh also teaches the relevance of what it terms Glioma stems cells (GSCs) as a source of resistance, pages 19-20, noting also in Figure 1 legend that “the criteria for defining GSCs are still evolving….”. There is nothing in applicant statements regarding the “unreachability” of glioblastoma tumor cells with stem cell properties (CSCs, also referred to on page 6 of 2/17/26 as “cancer stem cell”, as a subset of glioblastoma cells), nor any evidence found in the examples or elsewhere in the application as filed, that the instantly claimed administering of SEQ ID Nos: 2 or 3 or their salts is effective to improve (such as with statistical significance) the ability of TMZ or another therapeutic agent to specifically penetrate the glycocalyx surrounding CSCs or GSCs and/or reach and kill (such as with statistical significance) GSCs or CSCs relative to a control.
Apart from the above explanations for difficulty in effectively treating glioblastoma with TMZ, the examiner notes that there is no evidence in the application as filed, such as data from examples, that demonstrates any effect of the claimed compounds when administered to provide for uptake, or increased uptake, into CSCs. What is shown, at best, is uptake of doxorubicin into a number of glioblastoma cells shortly following AF-16 nasal administration that is stated to be more prevalent to uptake of doxorubicin preceded by nasal administration of control vehicle.
Specifically, the examiner does not find any specific statement in the application as filed to support applicant’s statement on page 6 that “The results of the experiments in the present application show that AF-16 enables uptake even in CSC cells in the glioblastoma tumor.” If referring to Example 4 (the only example that administered a therapeutic agent (apart from an antisecretory factor)), there is only reference to tumor cells, not stem cells nor CSC type cells (and also as to Example 4 the figures are not sufficiently clear to allow for distinguishing results between vehicle and AF-16). As such applicant’s line of reasoning as to effectiveness with regard to effects on CSCs is not persuasive. Additionally, the relevance of applicant’s rodent model of glioblastoma to the naturally progressing disease in a human subject, which may have very different architecture, also is a concern2.
Further to this point, the examiner does not dispute any relevance of a value in penetrating a biological barrier like the glycocalyx, in which applicant states the cancer stem cell subset resides, but does not see any evidence of achieving this in the experiments of the application as filed, nor any specific teaching of this with reasoning sufficient to indicate that what is claimed achieves this (also noting that this is not claimed).
To be blunt in conclusion of this response to arguments, the examiner does not find support in the application as filed for applicant’s statement on page 7, “Experimental results presented by the Applicant demonstrate that AF-16 uniquely enables TMZ uptake even in CSCs, a result that was not obvious or predictable based on prior art.” If such evidence exists, applicant may consider a very explicit indication of where this data is to be found in the application so that the examiner can consider it thoroughly.
Having considered and weighed the evidence, and statements from applicant, the examiner finds these unpersuasive when weighed against other evidence, the rejections’ references’ teachings, data and reasoning. Please also note the lack of relevant timing and amounts to achieve the claimed “facilitating and optimizing.”
The rejection under this section is as follows:
Claims 24, 31-34, 40-46 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Hansson et al. (WO 2010/093324; published 2010, of record), in view of Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record).
Claim 24 is directed to a method for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment, the method comprising administering to said patient a hexapeptide with an amino acid sequence CHSKTR as shown in SEQ. ID NO: 2 (AF-6), a peptide with an amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16), and/or a pharmaceutically active salt thereof; and thereby facilitating and optimizing uptake into glioblastoma cells of said pharmaceutical substance.
For this rejection, claim 24 is interpreted to require administering one of the claimed hexapeptide or peptide, and/or a pharmaceutically active salt thereof, prior to or with a pharmaceutical substance comprising an anti-glioblastoma drug, to a patient in need thereof, such administering in amount and time and type of administering is regarded sufficient for the claim 24 intended objective/result “for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment.” “Optimizing” is interpreted to mean “improving”.
The teachings of Hansson et al. are directed to antisecretory factor protein (AF) and peptide, derivatives, homologues, and/or fragments thereof (antisecretory factors). See the Abstract. Hansson et al. teach the fragment of antisecretory factor, AF-16, which has the amino acid sequence VCHSKTRSNPENNVGL, meeting the same in claim 24. See page 17, lines 7. Hansson et al. teach the fragments of antisecretory factor proteins disclosed therein all have analogous biological activity of being able to be used for the manufacture of a medicament for the food, and in methods of treating conditions such as tumors and tumor-related conditions. See page 26, line 34-page 27, line 2.3
Hansson et al. abundantly teach that the antisecretory factor protein of its invention (as well as shorter peptides including AF-16) is for “USE OF ANTISECRETORY FACTORS (AF) FOR OPTIMIZING CELLULAR UPTAKE,” Title, that uptake clearly including an anticancer drug, Abstract, the objectives including to optimize drug delivery, see page 3 line 34 through page 4 line 1, particularly page 10, lines 26-31, and also page 20 lines 3-10, and claims 1 and 2. Hansson et al. also teach that its antisecretory factor protein and/or fragments thereof can reduce pressure, such as intracellular pressure, page 1 lines 15-24, page 12, lines 29-36, as well as interstitial pressure, page 12, lines 16-27 and elsewhere. However, Hansson et al. teach that the effects on lowering IFP are transient, page 42, lines 29-34.
Hansson et al. provide data from their experiments that demonstrate reduction of pressure when administering AF-16, which as noted is identical to what is instantly claimed within claim 24. See Example 1, and also Example 2 in which tumor cell distribution of the anticancer drug doxorubicin is shown to be improved when rodents having MatB III tumors were pretreated by intranasal dosing 60 minutes prior to i.v. injection of the doxorubicin anticancer drug. From page 37, lines 33 to page 38, line 2, “The figures 5A/B and C/D, respectively, have the same density of tumor cells, but the specimen from an animal pretreated with AF-16 display strongly increased occurrences of red nuclei. This experiment thus revealed that AF-16 enables doxorubicin to reach close to every cells at sufficient concentration. We further conclude that these results indicated that AF-16 in addition facilitates the optimized delivery and/or cellular uptake of a low molecular weight drug into the individual cells of the tumor tissue.”
Hansson, however, does not explicitly nor specifically teach administering its peptides, such as AF-16, for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment.
The level of ordinary skill in the pertinent art is moderately high.
Iacob et al. teach the mainstay of therapy of glioblastoma (GBM) consists of surgery, radiation and chemotherapy.4 See page 389, §Treatment. Iacob et al. teach the objective of surgery is to alleviate symptoms including intracranial pressure (ICP). See page 389, §Treatment. Iacob et al. teach a survival advantage is provided to GBM subjects that receive TMZ (pharmaceutical substance/formulation; temozolomide) with standard radiation therapy (pharmaceutical substance/formulation). See page 389, §Treatment. Iacob et al. teach alkylating agents (pharmaceutical substance/formulation) like TMZ been demonstrated as beneficial and are used in the majority of GBM clinical protocols. See page 390, §Chemotherapy. Iacob et al. teach TMZ shows reduced toxicity towards normal cells, TMZ either concomitant with radiotherapy followed by adjuvant TMZ or as adjuvant TMZ alone after completion of radiation, is increasing the standard of care for GBM. See pages 390-391, §Chemotherapy.
Iacob et al. clearly teaches treating glioblastoma in a patient in need thereof with a pharmaceutical substance comprising an anti-glioblastoma drug, temozolomide (TMZ), as part of the standard of care, and teaches that an objective of surgery is to alleviate symptoms including intracranial pressure (ICP).
Given that Hansson teaches that administering its AF-16 peptide facilitates the optimized delivery and/or cellular uptake of a low molecular weight drug into the individual cells of the tumor tissue, and also can reduce pressure, such as intracellular pressure, one of ordinary skill in the art would reasonably combine the respective teachings to administer AF-16 peptide prior to administering TMZ with the objectives including to improve the effectiveness of TMZ in treating glioblastoma, such as by improving uptake of TMZ into glioblastoma cells. At the time the invention was made, it would have been obvious to the artisan of ordinary skill to administer AF-16 peptide, as taught by Hansson et al., in combination with the routinely administered anticancer drug temozolomide (TMZ), which per Iacob has been demonstrated as beneficial and are used in the majority of glioblastoma clinical protocols, in order to improve uptake of this anticancer drug and/or reduce pressures within the brain cavity and/or tumor. The rationale is combining prior art elements according to known methods to yield predictable results: the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference, one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately, and given the respective teachings and data, one of ordinary skill in the art would have recognized that the results of the combination were predictable. One of ordinary skill in the art would have been motivated to further administer TMZ, when combined with AF-16 such as by the latter’s appropriately timed pretreatment to improve uptake, with or without radiation therapy because it is has become the standard of care for GBM and TMZ with standard radiotherapy has been shown to provide a survival advantage to GBM patients. The addition of AF-16 or other related peptide, with AF-16 having been shown to improve doxorubicin uptake in cancer cells, would reasonably improve uptake of TMZ in one or more glioblastoma cells. The artisan would have had a reasonable expectation of success to administer TMZ and/or radiation therapy with AF-16 because AF-16 efficiently increases the penetration of cytostatic drug into tumor cell nuclei (and also potentiates the efficacy of radiotherapy (radiation) by lowering the interstitial fluid pressure (IFP) in tumor cells) as taught by Hansson et al. See page 42, lines 18-34.
Accordingly, claims 24, 31 and 32 would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3, claim 41 would have been obvious.
Based on the rejection of claims 24 and 41 and Hansson teaching in situ administration, page 24, lines 13-15, claim 33 would have been obvious.
Hansson et al. teach the pharmaceutical compositions can be administered through a surgically inserted shunt into a cerebral ventricle in the patient. See page 31, lines 36-37. In view of this teaching and the teachings of the references applied to claims 24 and 41, claim 34 would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3, as well as teachings with regard to medical food, such as on page 33, line 30 to page 34 line 4, the last sentence also stating “Said administration can be performed either as a single dose or as multiple daily applications,” claim 40, and also claim 45, would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3 and 6, claim 42 would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3 and 7, claim 43 would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3 and 8, claim 44 would have been obvious.
Based on the rejection of claim 24 and Hansson’s claims 1-3 and 11, claim 46 would have been obvious.
Therefore, at the time the invention was made, the claimed invention was prima facie obvious to the artisan of ordinary skill.
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 24, 31-34, and 40-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3,4, 6-8, 11-13 and 17 of U.S. Patent No. 9220750 (reference patent) in view of in view of Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record).
Claim 24 is directed to a method for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment, the method comprising administering to said patient a hexapeptide with an amino acid sequence CHSKTR as shown in SEQ. ID NO: 2 (AF-6), a peptide with an amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16), and/or a pharmaceutically active salt thereof; and thereby facilitating and optimizing uptake into glioblastoma cells of said pharmaceutical substance.
Reference patent claim 1 similarly is directed to “A method for optimizing cellular uptake of a pharmaceutical substance and/or formulation, said method comprising administering to a subject a pharmaceutical composition comprising: a) an antisecretory factor (AF) protein; a derivative, homologue and/or fragment thereof having AF activity; and/or a pharmaceutically active salt thereof in an amount sufficient to induce normalization and/or reduction of the intracellular pressure in a pathological cell for optimizing cellular uptake of a further pharmaceutical substance, and b) a further pharmaceutical substance selected from the group consisting of anticancer drugs, cytostaticas, antimicrobial substances, antibiotic substances, antiviral substances, antibodies, drugs targeting a posttraumatic injury, drugs targeting neurodegeneration, drugs targeting a parasite, and drugs targeting an inflammatory condition,” its claim 3 sets forth a genus of AF proteins and fragments that include AF-16 (X5 is amino acids 43-51 of SEQ ID NO:6, also considering reference patent claim 13, where such requires that it comprises at least the amino acid sequence of SEQ ID NO: 4, which is CHSKTR, this the other peptide of instant claim 24, so both of claim 24 peptides are reasonably identified), however the particular target and drug of instant claim 24 are not explicitly claimed in the reference patent.
The level of ordinary skill in the pertinent art is moderately high.
Iacob et al. teach the mainstay of therapy of glioblastoma (GBM) consists of surgery, radiation and chemotherapy.5 See page 389, §Treatment. Iacob et al. teach the objective of surgery is to alleviate symptoms including intracranial pressure (ICP). See page 389, §Treatment. Iacob et al. teach a survival advantage is provided to GBM subjects that receive TMZ (pharmaceutical substance/formulation; temozolomide) with standard radiation therapy (pharmaceutical substance/formulation). See page 389, §Treatment. Iacob et al. teach alkylating agents (pharmaceutical substance/formulation) like TMZ been demonstrated as beneficial and are used in the majority of GBM clinical protocols. See page 390, §Chemotherapy. Iacob et al. teach TMZ shows reduced toxicity towards normal cells, TMZ either concomitant with radiotherapy followed by adjuvant TMZ or as adjuvant TMZ alone after completion of radiation, is increasing the standard of care for GBM. See pages 390-391, §Chemotherapy.
Iacob et al. clearly teaches treating glioblastoma in a patient in need thereof with a pharmaceutical substance comprising an anti-glioblastoma drug, temozolomide (TMZ), as part of the standard of care, and teaches that an objective of surgery is to alleviate symptoms including intracranial pressure (ICP).
Given that reference patent claims administer AF-16 peptide for optimizing the uptake of a pharmaceutical substance including an anticancer drug, one of ordinary skill in the art would reasonably be motivated to administer AF-16 peptide prior to administering TMZ with the objectives including to improve the effectiveness of TMZ in treating glioblastoma, such as by improving uptake of TMZ into glioblastoma cells. At the time the invention was made, it would have been obvious to the artisan of ordinary skill to administer AF-16 peptide of reference patent claims 1, 3 and 13, or simply CHSKTR peptide per the same claims, in combination with the routinely administered anticancer drug temozolomide (TMZ), which per Iacob has been demonstrated as beneficial and are used in the majority of glioblastoma clinical protocols, in order to improve uptake of this anticancer drug and/or reduce pressures within the brain cavity and/or tumor. Please also note that reference patent claim 17 narrows the further pharmaceutical substance but includes in that narrowed list of three anticancer drugs and radiation therapy, both taught by Iacob for treatment of glioblastoma. The rationale is combining prior art elements according to known methods to yield predictable results: the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference, one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately, and given the respective teachings and data, one of ordinary skill in the art would have recognized that the results of the combination were predictable. One of ordinary skill in the art would have been motivated to further administer TMZ, when combined with AF-16 such as by the latter’s appropriately timed pretreatment to improve uptake, with or without radiation therapy because it is has become the standard of care for GBM and TMZ with standard radiotherapy has been shown to provide a survival advantage to GBM patients, and both were in the narrower list of reference patent claim 17. The addition of AF-16 or the other instantly claimed peptide, per reference patent claims 1, 3, 13 and 17 would reasonably be expected to improve uptake of TMZ in one or more glioblastoma cells. The artisan would have had a reasonable expectation of success to administer TMZ and/or radiation therapy with AF-16 or CHSKTR based on the reference patent claim 1 being clearly directed to optimizing cellular uptake.
Accordingly, claims 24, 31 and 32 would have been obvious and are rejected under this section.
Based on the rejection of claim 24 and reference patent claim 6, claims 41 and 42 would have been obvious and are rejected under this section.
Based on the rejection of claims 24 and 41 and reference patent claim 7 (including local administration), claim 33 would have been obvious and is rejected under this section.
Based on the rejection of claims 24 and 41 and reference patent claim 7 (including local administration), and in view of the meaning of local administering including through a surgically inserted shunt into a cerebral ventricle of the patient, see reference patent para 92, claim 34 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent claim 12, and Iacob teaching that TMZ crosses the blood brain barrier and can be administered orally, pages 389-390, claim 40 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent claim 7, claim 43 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent claim 8, claim 44 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent claim 11, claim 45 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent claim 12, claim 46 would have been obvious and is rejected under this section.
Claims 24, 31-34, and 40-46 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-3 of U.S. Patent No. 9962424 (reference patent) in view of in view of Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record) and U.S PGPUB No. 20120093716.
Claim 24 is directed to a method for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment, the method comprising administering to said patient a hexapeptide with an amino acid sequence CHSKTR as shown in SEQ. ID NO: 2 (AF-6), a peptide with an amino acid sequence VCHSKTRSNPENNVGL as shown in SEQ ID NO: 3 (AF-16), and/or a pharmaceutically active salt thereof; and thereby facilitating and optimizing uptake into glioblastoma cells of said pharmaceutical substance.
In Sun Pharmaceutical Industries Ltd. v. Eli Lilly and Co., 95 USPQ2d 1797 (Fed. Cir. 2010), the Court determined that claims of a later patent were held invalid for obviousness-type double patenting when the earlier patent claimed a compound and disclosed its utility in its specification, and later patent claimed a method of using the compound for a use described in the specification of the earlier patent.
Please note that the specifications of U.S. Patent No. 9962424 and the secondary reference U.S PGPUB No. 20120093716 are directed to the same methods of using the claimed peptide of instant SEQ ID NO:2 (AF-6), however the paragraph numbering of the same paragraphs differs in some versions of the texts. The ‘716 is applied to further support bases for rejection.
Reference patent claim 1 is directed to composition comprising the amino acid sequence consisting of SEQ ID NO: 4 or a pharmaceutically acceptable salt thereof in combination with a non-peptidic low molecular weight drug which is cytotoxic or cytostatic.
SEQ ID NO:4 of the reference patent is CHSKTR, the same as instant SEQ ID NO:2.
The specification of the reference patent (and also the ‘716 secondary reference) teaches methods for optimizing delivery and cellular uptake of a pharmaceutical substance and/or formulation, which typically comprises an anticancer drug, radiation therapy, an antibiotic substance, an antiviral substance or a drug targeting sequels of posttraumatic brain injuries, neurodegeneration, a parasite, or an inflammatory condition, first para of Field of Invention, and elsewhere including first paras of Summary of the Present Invention.
The reference patent does not claim or disclose such methods specifically applied for facilitating and optimizing uptake into glioblastoma cells of a pharmaceutical substance comprising an anti-glioblastoma drug in a patient in need of such treatment.
The level of ordinary skill in the pertinent art is moderately high.
Iacob et al. teach the mainstay of therapy of glioblastoma (GBM) consists of surgery, radiation and chemotherapy.6 See page 389, §Treatment. Iacob et al. teach the objective of surgery is to alleviate symptoms including intracranial pressure (ICP). See page 389, §Treatment. Iacob et al. teach a survival advantage is provided to GBM subjects that receive TMZ (pharmaceutical substance/formulation; temozolomide) with standard radiation therapy (pharmaceutical substance/formulation). See page 389, §Treatment. Iacob et al. teach alkylating agents (pharmaceutical substance/formulation) like TMZ been demonstrated as beneficial and are used in the majority of GBM clinical protocols. See page 390, §Chemotherapy. Iacob et al. teach TMZ shows reduced toxicity towards normal cells, TMZ either concomitant with radiotherapy followed by adjuvant TMZ or as adjuvant TMZ alone after completion of radiation, is increasing the standard of care for GBM. See pages 390-391, §Chemotherapy.
Iacob et al. clearly teaches treating glioblastoma in a patient in need thereof with a pharmaceutical substance comprising an anti-glioblastoma drug, temozolomide (TMZ), as part of the standard of care, and teaches that an objective of surgery is to alleviate symptoms including intracranial pressure (ICP).
Given that reference patent claims a composition comprising the same hexapeptide, and both its specification and that of the ‘716 generally disclose methods for optimizing the uptake of a pharmaceutical substance including an anticancer drug, one of ordinary skill in the art would reasonably be motivated to administer the hexapeptide of instant SEQ ID NO:2 prior to administering TMZ with the objectives including to improve the effectiveness of TMZ in treating glioblastoma, such as by improving uptake of TMZ into glioblastoma cells. At the time the invention was made, it would have been obvious to the artisan of ordinary skill to administer the SEQ ID NO:2 hexapeptide of reference patent claim 1, in combination with the routinely administered anticancer drug temozolomide (TMZ), which per Iacob has been demonstrated as beneficial and are used in the majority of glioblastoma clinical protocols, in order to improve uptake of this anticancer drug and/or reduce pressures within the brain cavity and/or tumor. The rationale is combining prior art elements according to known methods to yield predictable results: the prior art included each element claimed, although not necessarily in a single prior art reference, with the only difference between the claimed invention and the prior art being the lack of actual combination of the elements in a single prior art reference, one of ordinary skill in the art could have combined the elements as claimed by known methods, and that in combination, each element merely performs the same function as it does separately, and given the respective teachings and data, one of ordinary skill in the art would have recognized that the results of the combination were predictable. One of ordinary skill in the art would have been motivated to further administer TMZ, when combined with the SEQ ID NO:2 hexapeptide such as by the latter’s appropriately timed pretreatment to improve uptake, with or without radiation therapy because it is has become the standard of care for GBM and TMZ with standard radiotherapy has been shown to provide a survival advantage to GBM patients. The addition of the SEQ ID NO:2 hexapeptide would reasonably be expected to improve uptake of TMZ into one or more glioblastoma cells. The artisan would have had a reasonable expectation of success to administer TMZ and/or radiation therapy with the SEQ ID NO:2 hexapeptide CHSKTR based on the reference patent claim 1 being clearly teaching this in combination with a non-peptidic low molecular weight drug which is cytotoxic or cytostatic. Reference patent claim 1 itself, when considered in light of the teachings of Iacob, suggests a combination that would include TMZ when treating glioblastoma.
Accordingly, claims 24, 31, 32, and 41 would have been obvious and are rejected under this section.
Based on the rejection of claim 24 and reference patent claims 2 and 3, claim 42 would have been obvious and are rejected under this section.
Based on the rejection of claims 24 and 41 and disclosure and teachings in the reference patent and the ‘716, respectively, see paras 58 and 102 respectively, claim 33 would have been obvious and is rejected under this section.
Based on the rejection of claims 24 and 41 and reference patent claim 7 (including local administration), and in view of the meaning of local administering including through a surgically inserted shunt into a cerebral ventricle of the patient, see reference patent para 95, and also para 141 of the ‘716, claims 34 and 43 would have been obvious and are rejected under this section.
Based on the rejection of claim 24, para 35 of the reference patent, para 79 of the ‘716, and Iacob teaching that TMZ crosses the blood brain barrier and can be administered orally, pages 389-390, claim 40 would have been obvious and is rejected under this section.
Based on the rejection of claim 24 and reference patent para 56 and para 100 of the ‘716, claims 44 and 45 would have been obvious and are rejected under this section.
Based on the rejection of claim 24 and reference patent para 98 and para 144 of the ‘716, claim 46 would have been obvious and is rejected under this section.
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Primary Examiner, Art Unit 1658
1 For the record, the “SPC” administered in withdrawn claim 25 is the abbreviation for “Specially Processed Cereals” per Abbreviations on page 9 of the specification. This is distinct from administering the two particular claim 24 peptides corresponding to SEQ ID Nos. 2 and 3.
2 See pages 3-4 of Stine and Munson, Frontiers in Oncology, Oct. 2019, vol. 9, article 966, copy provided.
3 For clarity, the full relevant passage is “Homologues, derivatives and fragments of antisecretory factor (AF) proteins and/or peptides according to the present invention all have analogous biological activity of being able to be used for the manufacture of a medicament for the food for optimizing delivery and/or cellular uptake of a further pharmaceutical substance and/or formulation, as well as in a method for treating conditions such as tumors and tumor-related conditions, infections, inflammations and/or conditions caused by parasites.”
4 Underlining is added in part to further address applicant arguments. Please note that “therapy” is reasonably understood to include treating, so surgical therapy to reduce ICP is treating GBM.
5 Underlining is added in part to further address applicant arguments. Please note that “therapy” is reasonably understood to include treating, so surgical therapy to reduce ICP is treating GBM.
6 Underlining is added in part to further address applicant arguments. Please note that “therapy” is reasonably understood to include treating, so surgical therapy to reduce ICP is treating GBM.
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