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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 9/13/24 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Claims 25, 26, 36 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b), as being drawn to a nonelected invention there being no allowable generic or linking claim.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 1 RCE-type filing 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 6/9/25 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Claims 25, 26, 36 and 37 are withdrawn from further consideration pursuant to 37 CFR 1.142(b). Claims 24, 31-34, and 40-46 are under examination.
Claims 24, 31-34, and 40-46 are rejected.
Claim Interpretation
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.
Claim Rejections - 35 USC § 112(b)
Response to Arguments
Applicant’s arguments, see page 5, filed 6/9/25, and claim amendments, with respect to the rejection(s) of claim(s) 31-34, 40 and 41 rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite have been fully considered and are persuasive. Therefore, the rejection has been withdrawn.
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.
Claims 24, 31-34, 40-46 are rejected under pre-AIA 35 U.S.C. 103(a) as being unpatentable over Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record) in view of Hansson et al. (WO 2010/093324; published 2010, of record), and Jennische et al., “The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increased of intracranial pressure”, Brand Research 1227, 2008, pp. 189-197; of record.
Response to Affidavits and Applicant Arguments
The Declaration under 37 CFR 1.132 filed 6/9/25, four pages, is insufficient to overcome the rejection of claims 24, 31-34, 40-46 rejected under pre-AIA 35 U.S.C. 103(a) based on Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record) in view of Hansson et al. (WO 2010/093324; published 2010, of record), and Jennische et al., “The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increased of intracranial pressure”, Brand Research 1227, 2008, pp. 189-197; of record, as set forth in the last Office action because: Meijer, referenced and criticized by Declarant in paragraphs 2 and 3, and Boucher, referenced and criticized by Declarant in paragraphs 4 and 5, with both of these references also referred to in paragraph 6, are not applied in the most previous 35 USC 103 rejections, in the 1/8/25 Non-final rejection. Therefore arguments against these references are neither relevant nor persuasive. Paragraphs 7-13 provide statements and opinions regarding the effect of IFP (interstitial fluid pressure), including non-claimed agents that may reduce IFP, including statement of serious side effects, and also hyperventilation, and in paragraph 13 hypothesizes “there are several putative effects of antisecretory factor (AF) protein that could act in synergy with chemotherapy.” All of this is unpersuasive because many statements are not relevant to what is being claimed, nor to teachings of the cited references, and also specifically because what is claimed is administering two peptides, not AF protein. Paragraphs 14, 15 and 17 also refer to possible (or likely per para 17) interactions and effects without providing data, so also are unpersuasive.
The Declaration under 37 CFR 1.132 filed 6/9/25, two pages, is insufficient to overcome the rejection of claims 24, 31-34, 40-46 rejected under pre-AIA 35 U.S.C. 103(a) based on Iacob et al. (“Current data and strategy in glioblastoma multiforme”, Journal of Medicine and Life, 2009, pp. 386-393, of record) in view of Hansson et al. (WO 2010/093324; published 2010, of record), and Jennische et al., “The peptide AF-16 abolishes sickness and death at experimental encephalitis by reducing increased of intracranial pressure”, Brand Research 1227, 2008, pp. 189-197; of record, as set forth in the last Office action because:
Regarding paragraph 2, glioma is not instantly claimed, so the statement as to AF (not stating whether this means the AF protein or one of the claimed peptides) prolonging survival of experimental animals with glioma do not appear dispositive nor entitled to substantial weight as to what is instantly claimed, this including because there is a question of a nexus, see MPEP 71.01(b), and also because no data is provided;
Regarding paragraph 3, no data is provided, so the weight attributed to statements in this paragraph including curing “up to 90% of tumor bearing animals” by AF plus chemotherapy (again AF not clearly aligned with what is claimed – is this the protein or a claimed peptide?), is not high.
Regarding paragraph 4, the examiner has weighed the Declarant’s opinion.
Regarding paragraph 5, the examiner notes and has weighed this statement regarding “we” not having found any proof that AF-16 lowers the IFP in experimental tumors, and also notes that Examples 1-3 of the specification determine reduction in IFP after administering a claimed AF peptide, however this apparently measuring IFP outside of the tumors themselves.
Applicant's arguments filed 6/9/25 have been fully considered but they are not persuasive.
Applicant first argues that “The examiner’s citation of Iacob reveals a fundamental flaw in the rejection,” because the rejection is “thus based, at least in part, on the incorrect conclusion that part of what AF does is to lower ICP in the glioblastoma patient, which provides some relief for patients with glioblastoma. Even if that were true, such a relief is not treatment of the underlying glioblastoma, but only relieves secondary symptoms.” Even apart from the bases set forth in the rejection below as to bases for treating glioblastoma with the claimed AF peptides, applicant’s specification on page 4 states
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The last sentence particularly further supports that lowering IFP in the brain cavity of a glioblastoma patient would be treating the disease of glioblastoma because this would reasonably be expected to extend the life of such patient, even if only for a period of days or weeks, even if this lowering of IFP is apart from IFP within the tumor.
Please also note that the examiner’s rejection can have a different basis for effectiveness of treatment than that identified or proposed by applicant.
As to the statement that glioblastoma cells “differ in critical aspects from other cancer cells; these differences mean that it is almost impossible to get TMZ or any other drug into these cells,” page 7. The examiner has weighed this statement against statements in Iacob et al. that TMZ is part of the standard of care, so is persuaded based on TMZ’s inclusion in the standard of care that at least some TMZ does get into glioblastoma cells. Also the combination of references provides a basis based on lowering cranial IFP that reasonably would increase drug uptake into glioblastoma cells, see rejection below.
As to the presence and persistence of tumor cells with stem cell properties in a glycocalyxed glioblastoma tumor, this is not dispositive because the only requirement is treating, which includes extending life span even if by a short period, and curing is neither claimed nor demonstrated with evidence.
Please also note that neither penetration of a glycocalyx nor uptake of a drug by a cancer stem cell are claimed, nor does the examiner find a clear basis of support at least for the latter in the application as filed.
Regarding uptake of TMZ by a cancer stem cell, and statements on page 8, first full paragraph, Examples 1-3 pertain to IFP in rodents, and Example 4 evaluates the uptake of doxorubicin, not TMZ, when also administered with AF-16. If applicant wishes for the examiner to consider data, including as AF-16 plus chemotherapy curing up to 90% of tumor bearing animals in a rodent model (as referenced at para 3 of the 2 page Declaration), this data must be presented, and for improved weight of consideration provided with a description of the methods and results that include relevant positive and negative controls.
Having weighed the evidence, opinions, and statements set forth by Applicant and Declarant in the two Declaration, as well as considering implications and/or inferences with regard to the Declarant’s statements, the examiner finds these unpersuasive when weighed against the rejections’ reference’s teachings, data and reasoning.
Finally, as previously stated, Applicant has not explicitly articulated why, even given the glycocalyx, at least a de minimis degree of drug transport improvement would not be achieved in view of the art and the known mechanisms.
The rejection under this section is as follows:
Claim 24 is directed to a method for treating glioblastoma, characterized by administering 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 a further pharmaceutical substance and/or formulation comprising an anti-glioblastoma drug; to a patient in need thereof
For this rejection, claim 24 is interpreted to require administering one of the claimed hexapeptide or peptide, and/or a pharmaceutically active salt thereof, in combination with a further formulation comprising an anti-glioblastoma drug, to a patient in need thereof.
Iacob et al. teach the mainstay of therapy of glioblastoma (GBM) consists of surgery, radiation and chemotherapy.2 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, but does not teach administering 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 the patient in need of treating the glioblastoma as claimed.
However, 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, 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 is for “USE OF ANTISECRETORY FACTORS (AF) FOR OPTIMIZING CELLULAR UPTAKE,” 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.
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 with regard to increased uptake of an anticancer drug.
Additionally as to relieving pressure, Jennische et al. teach the peptide AF-16, comprising the amino terminal part of the endogenous Antisecretory Factor (AF), suppresses raised intracranial pressure while concomitantly eliminating the deleterious, high pressure peaks. See the abstract, page 190, right col-1st paragraph and page 194, right col., 2nd paragraph. Jennische et al. further teach the results of their experiments advocate that AF-16 is a promising candidate drug in the search for therapeutics against increased ICP in humans. See page 194, right col., 2nd paragraph.
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., as well as by Jennische 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 artisan of ordinary skill in the art would have been motivated to further administer TMZ 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 artisan would have been motivated with 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 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.
Conclusion
No claim is allowed.
THIS ACTION IS MADE FINAL. 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 JOSEPH FISCHER whose telephone number is (571)270-7925. The examiner can normally be reached M-F 9am-5pm.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached on 571-270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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/JOSEPH FISCHER/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 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.
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.”
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