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 .
THIS IS A SECOND NON-FINAL OFFICE ACTION.
Election/Restrictions
Applicant’s election without traverse of Group I, claims 1-16 in the reply filed on 8/6/24 is acknowledged.
Claims 17-31 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/6/24.
Applicant elected the species of larazotide of SEQ ID NO:1, without traverse, on 8/6/24.
Applicant also elected (ii) a route of administration to the gastrointestinal tract in a sustained release formulation, without traverse, (iii) administration 3 times per day and throughout a checkpoint inhibitor therapy regimen, without traverse.
Claims 1, 4-16 read on the elected species.
Claim 2 and 3 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/6/24.
The examiner has reconsidered the restriction of inventions and has withdrawn this basis for restriction, and maintains the species election requirement. Based on the species election, claims 17-31, being drawn to a nonelected species, remain withdrawn.
Claim Status
Claims 1-8, 10-22, 24-32 are pending.
Claims 9 and 23 are cancelled.
Claims 17-31 had been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/6/24. Claims 17-22 and 24-31 remain withdrawn as being drawn to a nonelected species.
Claim 2 and 3 had been withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected species, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 8/6/24.
Claims 1, 4-8, 10-16 and 32 are pending and under examination.
Claims 1, 4-8, 10-16 and 32 are rejected.
Priority
The instant application, filed 02/10/2021 is a Continuation in Part of 16982115 , filed 09/18/2020, now abandoned
16982115 is a National Stage entry of PCT/US2019/022885 , International Filing Date: 03/19/2019
PCT/US2019/022885 Claims Priority from Provisional Application 62644723 , filed 03/19/2018.
Please also note: 17239056 filed on 04/23/2021, now U.S. Patent #11278587 is a Continuation of instant 17172387, filed on 02/10/2021.
Specification
Response to Arguments
Applicant’s arguments, see page 7, filed 7/7/25, and specification/title amendments, with respect to the objections have been fully considered and are persuasive. The objections to the specification and to the title has been withdrawn.
Drawings
Applicant’s arguments, see page 7, filed 7/7/25, and drawings amendments, with respect to the objections have been fully considered and are persuasive. The objection to the drawings has been withdrawn.
Claim Interpretation
Claim 1 as amended 7/7/25 and claims depending from it are drawn to treating cancer, comprising administering to the gastrointestinal tract of a patient in need thereof and undergoing therapy with one or more immune checkpoint inhibitors an effective amount of larazotide or a larazotide derivative thereof having the amino acid sequence of SEQ ID NO:1 with one or more (d) amino acids.
It is noted that the peptide of claim SEQ ID NO:1 has been used to treat other diseases, such as Crohn’s disease (e.g., US 8796203), whereas the instant specification is solely directed to the treatment of cancer.
The elected route of administration to the gastrointestinal (“GI”) tract in a sustained release formulation is understood to be an administration of a sustained release formulation through oral ingestion. Sustained release formulation is described in the specification as “slow release of the larazotide or a derivative thereof in the GI tract over an extended period of time,” and as further stated, ”Sustained release formulations will allow the composition to be applied at larger portions of the GI tract, while avoiding loss of efficacy from an inverse dose response observed with larazotide,” both from para 10 (also see para 43). Based on the claim dependency structure, claim 13 depending from claim 12, sustained release formulation is interpreted as a type of delayed release capsules that provides slow release over an extended period of time, see also Ghule and Aher, INTERNATIONAL JOURNAL OF PHARMACEUTICS & DRUG ANALYSIS, VOL.5 ISSUE 5, 2017; 153 – 160, previously provided.
Claim Rejections - 35 USC § 112(b)
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.
Response to Arguments
Applicant’s arguments, see page 8, filed 7/7/25, and claim amendments, with respect to the rejection(s) of claim(s) 1, 4-16 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. However, upon further consideration, new ground(s) and modified bases of rejection are made in view of the claim amendments.
Claim 1, 4-8, 10-16 and 32 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.
There are two bases for rejection under this section:
Claim 1’s method recites administering an effective amount of larazotide or a larazotide derivative having the amino acid sequence of SEQ ID NO:1 with one or more (d) amino acids. However, the amino acids of larazotide, corresponding to SEQ ID NO:1, are (l) amino acids. Therefore, SEQ ID NO:1 cannot have (d)-amino acids. For amino acid sequences, according to 37 C.F.R. 1.821(a)(2): “Amino acids are those L-amino acids commonly found in naturally occurring proteins and are listed in WIPO Standard ST.25 (1998), Appendix 2, Table 3.” It appears the general intention was to mean: wherein the peptide has least one amino acid substituted with the same amino acid which is a (d)-amino acid. Further in this regard, it is unclear if the substitution is of the same amino acid but in the (d)-form or is a different amino acid, and if the (d) amino acid is substituted from an amino acid with SEQ ID NO:1 or merely within a larger peptide comprising the amino acid sequence of SEQ ID NO:1, this based on the claim’s “having” interpreted as an open transition synonymous with “comprising”. As a result, the metes and bounds are unclear and cannot be determined.
Although claim 1 has been narrowed, now directed to a method of treating cancer, and although as previously recited from MPEP 2173.04, that “breadth is not indefiniteness,” so that applicant generally is free to claim broadly, here the metes and bounds of the “effective amount” remain unclear because it is not clear whether the administered larazotide or a derivative thereof, as claimed in claim 1, is treating cancer directly, or is potentiating the one or more immune checkpoint therapy/therapies that the patient is undergoing.
Claim 1 accordingly is rejected under this section, as are claims 4-8, 10-16 and 32 which depend from claim 1 and do not resolve these bases.
Claim Rejections - 35 USC § 112(a)
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 1, 4-8, 10-16 and 32 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for a method of treating cancer in a patient comprising administering to the gastrointestinal (GI) tract of said patient an effective amount of a peptide having the amino acid sequence of SEQ ID NO:1 or a pharmaceutically acceptable salt thereof, wherein it is “(d)-larazotide (INN-202)”, in combination with an anti-PD1 and/or anti CTLA-4 antagonist antibody immune checkpoint inhibitor, does not reasonably provide enablement for wherein the derivative of larazotide (SEQ ID NO:1) is not (d)-larazotide – (the latter interpreted herein as having all d-form amino acids except for glycines), and wherein it is not combined with an anti-PD1 and/or anti CTLA-4 antagonist antibody immune checkpoint inhibitor. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention commensurate in scope with these claims.
The factors considered when determining if the disclosure satisfies the enablement requirement and whether any necessary experimentation is undue include, but are not limited to: 1) nature of the invention, 2) state of the prior art, 3) relative skill of those in the art, 4) level of predictability in the art, 5) existence of working examples, 6) breadth of claims, 7) amount of direction or guidance by the inventor, and 8) quantity of experimentation needed to make or use the invention. In re Wands, 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
Claim 1 is drawn to a method of treating cancer comprising administering to the gastrointestinal tract of a patient in need thereof and undergoing therapy with one or more immune checkpoint inhibitors an effective amount of larazotide or a larazotide derivative thereof having the amino acid sequence of SEQ ID NO:1 with one or more (d) amino acids. The nature of the invention is medical therapeutic methods, and although there is a reasonable level of predictability as to the ability of appropriately administered larazotide to act upon tight junctions by known mechanisms, such as to treat celiac disease, there is a low level of predictability for modification of peptides administered for medical therapies, this notwithstanding that the general level of skill of those in the art is moderately high, those persons having advanced degrees in medicinal chemistry, organic chemistry, and/or medicine with at least two years of experience in the field.
There are several issues of enablement. One has to do with “(d)-larazotide” per se. Another involves which drug(s), alone or in combination, can be used in the claimed method. A third with what the larazotide or derivative thereof as claimed is treating when administered in its effective amount. Finally, how the peptide is administered is also not fully enabled, this including the issue of administering by approaches other than the administering of a peptide.
First, as to independent claim 1 when administering an effective amount of “a larazotide derivative thereof having the amino acid sequence of SEQ ID NO:1 with one or more (d)-amino acids”, it is not required that the (d)-amino acid be the same amino acid as the (l)-amino acid of SEQ ID NO:1. That is, it is not required that the (l)-proline be replaced by a (d)-proline. Indeed, there can be additional amino acids added to the octapeptide of SEQ ID NO:1, since administration is of a peptide having that sequence, where “having” is open language and is synonymous with comprising. So the administered peptide could be larger than that of SEQ ID NO:1 and/or could have one or more of any (d)-amino acids substituted for the specific (l)-amino acid of SEQ ID NO:1. While the specification lists derivatives of SEQ ID NO:1, it does not provide a reasonable expectation that such derivatives could be used in the instant method of treatment.
Additionally, while the Examples and Figures show data from experiments using (d)-larazotide (INN-202) (see e.g., p. 3, line 23), it is not clear what exactly that drug is and, so, what was used in the experiments. The specification (p. 5, lines 6-7), defines larazotide as “larazotide or a derivative that promotes tight junction integrity.” Derivatives are further defined (p. 4, lines 33-35) as comprising “one to five amino acid … modifications with respect to SEQ ID NO:1, and the modifications may be independently selected from substitutions, deletions, insertions or additions with respect to SEQ ID NO:1.” Note the word “comprising” is not closed language and allows for more. (d)-larazotide is described as a larazotide derivative (p. 9, line 33). On page 5, lines 33-34, it is stated, “In some embodiments, the treatment is with (d)-larazotide, that is, where all non-glycine residues are in the (d) form.” However, it is not clear if the (d)-larazotide referred to as in the “(d)-larazotide (INN-202)” used in the experiments is the one where all non-glycine residues are the same amino acids but in the (d) form. As a result, one would not know how to make “(d)-larazotide” because it is not clear what it is.
The next issue of enablement deals with the method of treatment. First, it is noted that the method is for treating cancer, by administering an effective amount, to the gastrointestinal tract of a patient in need thereof and (the patient) undergoing therapy with one or more checkpoint inhibitors. There is a question as to whether the effective amount pertains to treating the cancer directly treating or to potentiating the one or more checkpoint inhibitors. Additionally, it does not appear that the peptide of SEQ ID NO:1 (larazotide) with least one (d)-amino acid can generally be used in the claimed method. Instead, it appears that treatment typically requires both (d)-larazotide (INN-202) and an anti-PD1 and/or anti-CTLA-4 antagonist antibody immune checkpoint inhibitor. As can be seen in Fig. 1B, while there is significant tumor growth inhibition by the anti-PD1 antibody alone or with larazotide, there is no significant difference that depends on the presence of larazotide. Fig 1C shows there is no significant difference between anti-PD1 antibody alone or with larazotide in an MCA205 fibrosarcoma subcutaneous orthotopic mouse model (i.p. drug administration (p. 15, lines 12-20). A closer look at the data (Fig. 1B) shows larazotide alone significantly inhibited tumor growth only for days 5 (where the control had two outliers and there is no comparison with aPD1) and 12, but not at days 16 and 19, after which there is no data. As shown in Figure 4C, there is no difference in tumor growth between water + control and INN-202 + control; although, there appears to be a difference beginning on the 5th day through 7th of the second Combo injection (days 13-15 after tumor cell injection; the anti-CTLA-4 and anti-PD1 antibodies together are referred to as “Combo” or “ICB”, see Figs. 2A-D description and titles), but unfortunately there is no further data for water or INN-02+control. This is in contrast to both controls being significantly different over time compared to treatment with either the anti-CTLA-4 and anti-PD1 antibodies together or INN-202+Combo (Fig. 4C). Similarly, Fig. 2C shows for a RET orthotopic melanoma mouse model treated with different groupings of drugs, only larazotide + Combo and INN-202+Combo resulted in survival past about 18 days. Fig. 2C (esp. bottom panel) shows that the Combo alone or with INN-202 produced the greatest reduction in tumor size, however, it is unclear why that bottom graph does not extend the Larazotide+Combo data to 20 days or at least 12 days for which the data of individual mice is shown in a separate graph for Fig. 2C. The early data for Fig. 2C is shown in Fig. 2B, about which the specification states (beginning p. 15, line 32), “The results showed that neither larazotide [nor] (d)-larazotide prevented the outgrowth of RET as a standalone therapy (see FIG 2B). Larazotide in fact tended to boost RET outgrowth within the first 1035 days, as compared to naive and control mice (see FIG 2B). However, the data shows that 48DB1/ 116598682.1 15 Attorney Docket No.: NMT-017CPC1/116031-5017hours after the second cICB administration, (d)-larazotide [INN-202] promptly and significantly decreased tumor progression compared to the control group or (d)-larazotide alone group (FIG 2B,C). The combination of (d)-larazotide and cICB was the only group prolonging overall survival and sustained anticancer effects (Fig. 2D).” From the results set forth in the specification taken together, it appears that for a reasonable expectation of successful treatment of cancer, both (d)-lazarotide (INN-202) in combination with at least a PD-1 inhibitor or z CTLA-4 inhibitor are required, as it reasonably appears based on instant disclosure and the known effectiveness of anti-PD-1 and anti-CTLA-4 inhibitors in the prior art (see Van den Eynde et al., Ann. Rev. Canc. Biol., 4:241-256, 2020).
Additionally, there is no reasonable expectation that other immune checkpoint inhibitors, such as DIO or TIM3, could be used in the claimed method. For example, Acharya et al. (J. Immunother. Canc. 8: e000911, pp. 1-11, 2020) explains that even after the filing date of the instant application the use of TIM3 a checkpoint inhibitor in the clinic is unclear. One such inhibitor has been used in mice in combination with an anti-PD1 antibody, and shown to reduce tumor progression (ABSRACT). However, there were initial reports that TIM3 was a costimulatory receptor, but more recently it was shown to be inhibitory (p. 9, col. 1, last paragraph). The mechanisms by which TIM3 exerts its influence have not been fully clarified, leading to the conclusion that (p. 9, col. 1, last paragraph), “Further elucidation of these key functions for TIM-3 will help guide clinical development.” Three years after the effective filing date of the instant invention, Van den Eynde et al. (Ann. Rev. Canc. Biol., 4:241-256, 2020) teach therapies with an inhibitor of immune checkpoint protein IDO1 failed in different phases of clinical trials (see pp. 242-244); even though, (p. 242, first sentence) “Immune checkpoint inhibitors such as the anti-PD1 antibodies nivolumab and pembrolizumab, and the anti-CTLA4 antibody ipilimumab, have dramatically changed the prognosis of patients with metastatic melanoma.” IDO1 inhibitors might have promise, but are not enabled for treatment of cancer commensurate in scope with the instant claims, and their activity in combination with larazotide would have been unpredictable.
Lastly, there is an issue of administration, that is, the step of administering in the claims. The term “administration” in the specification encompasses bacteriophage and microorganism delivery of polynucleotides encoding larazotide that infects microbes in the GI tract of the subject (p. 7, lines 22-29), as well as delivery of the peptide in formulations, such as delayed-release formulation, e.g., in a capsules (p. 8, last paragraph). The peptide of SEQ ID NO:1, called larazotide or AT-1001 in the acetate form, has successfully been administered orally as a capsule (US 9,279,807, col. 2, lines 13-32, and col. 33, lines 22-27). While exemplary bacteriophage are listed in the specification (e.g., p. 8, lines 5-6), there is insufficient direction or guidance to use a bacteriophage in this method to produce the peptide with one or more (d)-amino acid(s) and having a reasonable expectation of successfully producing the agent in a location and in an amount sufficient to treat a cancer (whether directly or by potentiating the immune checkpoint inhibitor(s)), particularly that is not a cancer of the GI tract, because, for example, there is no information on secretory peptides for export of the drug outside the cell or, if a lysogenic bacteriophage, the effect of continued production and spread of larazotide (since opening of TJ, which larazotide antagonizes, is a necessary and natural process for certain physiological actions, see US 9,279,807, col. 2, lines 13-32, US 8,785,374, col. 3, lines 31-46; and additionally Leech et al. (Ann. Trend Med. 3(13):184, 2015, p. 2/15, col. 1, second and third paragraphs)), or if a lytic bacteriophage the result of killing host cells, e.g., intestinal cells, in the patient. Further, Ju et al. (Drug. Deliv. 24:1, 1898-1908, Dec. 2017, published after the effective filing date of the instant application) discusses that even though there has been some success using bacteriophage for transport of agents in animal models, it is cautioned that, “Though progress on filamentous phage-based delivery system has been made during the past decades, the potential of this biomaterial needs further exploration…. As the research moves along, we believe that filamentous phage and phage-mimetic nanoparticles will play a crucial role for the development of precise and personal medicine.” These issues are the same or similar for delivery of larazotide expressed by probiotic strains of microorganisms (paragraph bridging pp. 6-7 of the specification). Namely that because the strain may be a bacterium or fungus, the consideration include how to obtain sufficient production of larazotide from the microorganism inside a patient, how to prevent negative effects of multiplication of the microorganism, the lack of direction or guidance related to these concerns or dosage necessary to obtain an effective amount and the lack of support by the prior art of this method of administration. It does not appear that of the effective filing date the instant invention, the skilled artisan would have had a reasonable expectation of success using bacteriophage or other microorganism comprising the encoding polynucleotide for the claimed method because of the complex issues in its therapeutic use, and given the lack of specific as opposed to general information and working examples in the specification, and the showing of post-filing art that bacteriophage use for peptide delivery was not well known or routine, it would have required undue experimentation to practice the claimed invention by this method. Therefore, only administration of the peptide and not the encoding nucleic acid, in any form, is enabled.
Claims 1, 4-8, 10-16 and 32 therefore are rejected on the above scope of enablement rejection.
Claims 1, 4-8, 10-16 and 32 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.
Based on the evidence and reasoning applied in the rejection immediately above, after reviewing the application as filed, the examiner finds that applicant is not in possession of treating cancer by potentiating an immune checkpoint inhibitor targeting immune checkpoints selected from PD-1, PD-L1 and CTLA-4 by administering to the gastrointestinal tract any form of larazotide and derivatives that include one or more (d)-form amino acids (interpreted to be substituted into SEQ ID NO:1 as the same amino acid in the same position in SEQ ID NO:1 but in (d)-form) other than the evaluated “INN-202”. And based on the data taken as a whole applicant is not in possession of any form of larazotide and its (d)-form derivatives for treating cancer directly, whether or not the cancer patient in need of therapy is undergoing an immune checkpoint inhibitor therapy.
Possession for the claimed methods is not what might be possible or achieved if one made or practiced the invention, but what is reasonably demonstrated or disclosed such that one skilled in the relevant art would understand that applicant is in possession of what is claimed. Where predictability is not high when changes are made to a therapeutic peptide, and there is a lack of sufficient data to guide what changes would reasonably be expected to result in achievement of a claimed method of therapeutic treatment, then applicant cannot reasonably be in possession of the range of peptides under consideration, here where any one or more of the SEQ ID NO:1 sequence amino acids are converted to the same respective amino acid in (d)-form, except for glycines.
The lack of possession is additionally supported by Slifer et al. (Am. J. Physiol. Gastrointest. Liver Physiol. 320:G983-G989, 2021), which is post-filing art that teaches that fragments of the octapeptide of instant SEQ ID NO:1 can inhibit the octapeptide’s activity. On p. G987, paragraph bridging cols. 1-2, it is discussed that, “The formation of LA inhibitory fragments presents a pharmacological dilemma, because it has the potential to limit efficacy of the parent LA molecule. To potentially prevent or slow down LA fragmentation by the brush-border enzymes responsible for LA fragmentation, chiral modification of the entire LA sequence to all D amino acids was conducted, which resulted in the generation of LA Analog 6 (A6) by Innovate Biopharmaceuticals, Inc. (now 9 Meters Biopharma, Inc.) (49, 50). Interestingly, A6 enhanced recovery of ischemia-injured jejunum at a 10-fold lower dose (0.1 μM) than the effective dose of LA in the same injury model (50). The brush-border enzyme fragmentation of A6 was significantly slower than LA. However, fragments of A6 were still detected with mass spectrometry analysis, and a high dose (10 µM) of one fragment did exhibit inhibitory effects on recovery when applied in tandem with A6 (0.1 µM).” Slifer et al. is cited to show that what form of larazotide is used for treatment is not a trivial consideration. This provides additional support as to the uncertainty as to the therapeutic effect of larazotide itself, and also of any derivative thereof that comprises one or more (d)-form amino acids substituted therein, because it is unknown and not predictable which of these derivatives would effectively reduce or eliminate the in vivo production of inhibitory fragments and provide an overall effective treatment for cancer or potentiation of the immune checkpoint inhibitor therapy in a cancer patient.
Accordingly, it is deemed that the specification fails to provide adequate written description for the method claims that administer the genus that encompasses larazotide and the claimed derivatives thereof and does not reasonably convey to one skilled in the relevant art that the inventor(s), at the time the application was filed, had possession of the entire scope of the claimed invention.
The specification fails to satisfy the written description requirement of 35 USC 112, first paragraph, and accordingly claims 1, 4-8, 10-16 and 32 are rejected under this section.
Claim Rejections - 35 USC § 103
Response to Arguments
Applicant’s arguments, see pages 9-10, filed 7/7/25, and claim amendments, with respect to the rejections of Claim(s) 1, 4-8 and 14-16 under 35 U.S.C. 103 over US 20110201543 in view of US 9539245 and Soubani et al., Jl. Of Critical Care 29 (2014) 183.e7-183.e12, of Claim(s) 1, 4-10 and 14-16 under 35 U.S.C. 103 over US 8034776, in view of Freeman et al., World J Gastroenterol 2009 April 7; 15(13): 1581-1583, and US 9539245, of Claim(s) 11-13 under 35 U.S.C. 103 over US 8034776, in view of Freeman et al., World J Gastroenterol 2009 April 7; 15(13): 1581-1583, US 9539245, and further in view of Ghule and Aher, INTERNATIONAL JOURNAL OF PHARMACEUTICS & DRUG ANALYSIS, VOL.5 ISSUE 5, 2017; 153 – 160 (GA), and of Claim(s) 1 and 4-16 under 35 U.S.C. 103 over US 8957032, in view of US 9539245, have been fully considered and are persuasive. These rejections have been withdrawn.
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.
Response to Arguments
Applicant’s arguments, see page 10-11, filed 7/7/25, with respect to the rejection(s) of claim(s) 1, 4-12 and 14-16 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 8957032 (Reference patent) in view of Freeman et al., World J Gastroenterol 2009 April 7; 15(13): 1581-1583 (Freeman) and US 9539245, inventor Peters, issued 1/10/17 (Peters), and claim 13 on the ground of nonstatutory double patenting as being unpatentable over claims 1 and 4 of U.S. Patent No. 8957032 (Reference patent) in view of Freeman et al., World J Gastroenterol 2009 April 7; 15(13): 1581-1583 (Freeman) and US 9539245, inventor Peters, issued 1/10/17 (Peters), as applied to claims 1 and 12 above, and further in view of Ghule and Aher, INTERNATIONAL JOURNAL OF PHARMACEUTICS & DRUG ANALYSIS, VOL.5 ISSUE 5, 2017; 153 – 160 (GA) have been fully considered and are persuasive. Therefore, the rejection has been withdrawn. However, upon further consideration, new ground(s) of rejection are made in view of claim amendments and reconsideration by the examiner.
Claims 1, 4-8, 10-16 and 32 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 9-11, 14, 15 and 21 of U.S. Patent No. 11278587. Although the claims at issue are not identical, they are not patentably distinct from each other because reference patent claim 1 is directed to treating cancer in a patient also undergoing an immune checkpoint inhibitor therapy targeting immune checkpoints, particularly selected from PD-1, PD-L1, and CTLA-4, by administering one of the species of larazotide (as best understood) encompassed by instant claim 1, specifically an immune checkpoint inhibitor therapy targeting immune checkpoints selected from PD-1, PD-L1, and CTLA-4. Essentially the administering is of a narrower subgenus comprising species encompassed by and anticipating the instant claim 1 broader scope a larazotide and particular derivatives thereof. Reference patent claim 2 makes obvious instant claims 4-6, reference patent claim 3 corresponds to instant claim 7, reference patent claim 4 corresponds to instant claim 8, reference patent claims 5-7, 9 and 10 overlap with and make obvious instant claims 10-13, reference patent claim 11 corresponds to instant claim 14, reference patent claim 15 corresponds to instant claim 15, reference patent claim 14 corresponds to instant claim 16, and reference patent claim 21 corresponds to instant claim 32.
Claims 1-8, 10-16, and 32 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 66 and 67 of copending Application No.17996228 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because reference application claim 66 is directed to a method for treating a subject having a neoplasm, comprising administering a pharmaceutical composition comprising the same subgenus of larazotide with one or more (d)-amino acids as instantly claimed, to the subject, and claim 67 depending from claim 66 states in part that the subject further receives cancer immunotherapy, this indicating or strongly suggesting that the neoplasm is a cancer. To understand the meaning of the reference claim 67 as to types of cancer immunotherapy, the specification includes immune checkpoint inhibitor therapy, examples of checkpoint inhibitor drugs include, but are not limited to, ipilimumab pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, and durvalumab, and in these embodiments the composition can be formulated for delivery to the GI as described herein, and also WO 2019/183036 (PCT of instant parent) is incorporated by reference in its entirety, para 89, and includes when cancer is a sarcoma, para 87, see also para 11. (See MPEP 804 II. B. 1, “ The portion of the specification of the reference that describes subject matter that falls within the scope of a reference claim may be relied upon to properly construe the scope of that claim.”)
Accordingly, claims 1-6, 8, 10-13, and 32 are rejected.
Additionally, as to claims 7 and 14-16, the frequency of administering, as well as the timing of administering one therapy relative to another therapy, similar to obviousness regarding optimization of concentration or temperature, see MPEP 2144 II.A, would have been obvious absent evidence of criticality of the particular frequencies and/or timings of administering, at least because one of ordinary skill in the art would have been motivated to vary the frequencies and relative timings and dosing of the administered agents having different functions to determine which protocols afforded superior results of overall outcome and patient comfort, and there would have been a reasonable expectation of success based on the known effects and side effects of the therapeutic agents.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Art Made of Record
The following prior art is considered pertinent to applicant's disclosure.
Martin et al. (Biochim. Biophys. Acta, 1788:872-891, 2009) discusses the role of tight junctions in cancer metastasis. While it reasonably appears tight junctions are involved, their role is complex and there are many protein that affect their function (see Table 1). It is concluded, “The TJ and changes in barrier function appear to be part of an essential mechanism that is awry during cancer metastasis; whether up-regulation promotes cell dissemination, or whether down-regulation, causing dismantling of the TJ structure leading to loss of polarity, loss of contact inhibition, uncontrolled growth, detachment and invasion of cancer cells and hence successful penetration of the endothelium (intravasation and extravasation) by aberrant cell surface expression (direct interaction) or via secretion of regulatory/degradative substances by the cancer cells.”
Leech et al. (Ann. Trend Med. 3(13):184, 2015, p.10/15) shows the state of the art as it relates to tight junction and their apparently contrasting roles in cancer, as well as lack of tight junction-directed treatments for cancer. As state in the paragraph bridging pages 9-10/15, “In conclusion, TJ proteins have a vast potential to both repress tumorigenesis (via the promotion of stable cell-cell adhesion) or to promote tumorigenesis (via adhesion-independent signal transduction events that control migration, proliferation and apoptosis)…. The development of therapeutic reagents against these proteins will pose challenges, not least how to avoid interfering with their intrinsic roles in normal physiology while consciously interrupting their contributions to cancer pathophysiology. However several parallel avenues of promising pre-clinical data support the possibility that this is an exciting path towards a future of targeted cancer therapies, once it is firmly underpinned by solid mechanistic investigations into the biology of how TJ molecules contribute to disease pathogenesis.”
Conclusion
No claim is allowed.
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/JOSEPH FISCHER/Examiner, Art Unit 1658