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 .
DETAILED ACTION
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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 of RCE on July 15, 2025 and amendment after final filed July 15, 2025 has been entered. Claims 1-14, 16-17, 19-24 were canceled, claim 15 was amended and claims 15, 18, 25-35 are pending in the instant application.
The restriction requirement was deemed proper and made FINAL in a previous office action. The restriction requirement was deemed proper and made FINAL in a previous office action. Claims 32-35 are withdrawn from consideration as being drawn to a non-elected invention.
Claims 15, 18, 25-31 are examined on the merits in this office action.
Withdrawn Objection
The objection to claim 15 is withdrawn in view of amendment of the claims filed July 15, 2025.
Maintained/Revised Rejections
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis (i.e., changing from AIA to pre-AIA ) for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The text of those sections of Title 35, U.S. Code not included in this action can be found in a prior Office action.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 15, 18, 25-31 remain rejected under 35 U.S.C. 103 as being unpatentable over Nock (US20150265732 A1, cited previously) in view of Eva ("Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231, cited in Applicant’s IDS) and Alargova (WO2018081521 A1, 10/27/2017 priority date).
Nock teaches a GRPR antagonist comprising a Radiometal, chelator, a spacer and a GRP receptor peptide antagonist meeting the limitations of the GRPR-antagonist of instant claim 15 (see claim 1) to be used for detection, imaging, diagnosis, targeting and treatment of cancers expression GRPR (see abstract). Regarding claim 15, Nock teaches the identical peptide as found in instant claim 15, (see SEQ ID NO:1 in claim 4), as the GRPR antagonist peptide (see claim 4). Nock teaches the identical compound of formula I (see paragraph 0048, paragraph 0111). Regarding claims 18 and 29, Nock teaches wherein the radiometal can be 177Lu or 68Ga (see paragraph 0032, claim 5, paragraph 0051).
Regarding claim 15, Nock teaches various concentrations of radioactivity. For example, Nock teaches Ga-67 had a concentration of 498-743 mCi/mL or 80 mCi/ML (see paragraph 0095). It is known that 1 mCi is equal to 37 MBq, thus, 498 mCi/mL is equal to 18,426 Mba/mL, 743 mCi/mL is equal to 27,4971 MBq/mL. Nock further teaches more than 95% peptide bound radioactivity, thus, the final amount is 17,504.7-26,116.45. Thus, meeting the limitations of instant claim 15.
Regarding claim 25, Nock teaches lowers concentrations of radioactivity (see paragraph 0094). For example, Nock teaches In-111 had a concentration of 10-20 mCi/mL (see paragraph 0094). It is known that 1 mCi is equal to 37 MBq, thus, 10 mCi/mL is equal to 37 Mbq/mL, 20 mCi/mL is equal to 740 MBq/mL. Nock further teaches more than 95% peptide bound radioactivity, thus, the final amount is 351.5 MBq/mL and 703 MBq/mL. Thus, meeting the limitations of instant claim 25
The amount of radioactivity is a result effective variable and it would have been obvious to optimize the amount to achieve optimal activity and labeling of the conjugate for the desired therapeutic purpose. Regarding claim 30, Nock teaches aqueous solution (see paragraph 0094, “dissolved in water”, see also paragraph 0101, saline). Regarding claim 31, Nock teaches a bolus infusion (see paragraph 0101).
Nock is silent to including a surfactant compound comprising a PEG15-HS. Nock does teach use of therapeutically effective excipients (see claim 19).
Eva teaches "Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231) discloses that surfactants are typically added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage. They have been shown to stabilize proteins, inhibit and prevent aggregation, and aid in protein refolding. Polysorbates 20 and 80 (Tween 20 and Tween 80, i.e. Surfactants comprising compounds having (i) a polyethylene glycol chain and (ii) a fatty acid ester) are the most commonly used nonionic surfactant excipients. They are widely reported to inhibit aggregation during stirring, shaking, freeze drying and freeze thawing and can significantly reduce protein adsorption on solid surfaces (See page 173 second paragraph, page 176 second paragraph). Eva teaches that non-ionic surfactants have been widely used to reduce protein adsorption on solid surfaces (see section 4.3.6) including polymers such as PEGs and Poloxamers (see page 178, second paragraph). Thus, use of nonionic surfactants including poloxamers such as kolliphor (also referred to as PEG 15HS), are competitive inhibitors of protein adsorption.
Eva discloses that nonionic surfactants such as Tween 20 and Tween 80 can reduce the adsorption of solid surfaces of proteins and, therefore, one skilled in the art can add them to compositions of radiolabeled GRPR-antagonists to reduce their adhesion depending on practical research purposes.
Alargova teaches that “Commonly used parenteral surfactant excipients such as Polysorbate 80 (Tween 80) and Polyoxyl 15 Hydroxystearate (solutol, Kolliphor HS 15) were evaluated to re-assemble and stabilize Conjugate 57 into organized micelles” (See paragraph 00334). Alargova teaches that “the formulation with Solutol showed slightly better PK properties compared to Tween” and improved stability of the conjugate (see paragraph 00339). Alargova additionally teaches “Polyoxyl 15 Hydroxystearate provided great stability to Conjugate 57 and was therefore chosen as a stabilizing and solubilizing excipient. Polyoxyl 15 Hydroxystearate is a water soluble non-ionic surfactant that is typically used in the formulations of pharmaceutical drugs which are poorly water soluble or to stabilize drugs. The concentration of Polyoxyl 15 Hydroxystearate used in the Conjugate 57 solution is between 1% to 10%, between 1% to 5%, or between 2% to 5% (weight percentage). In some embodiments, the concentration of Polyoxyl 15 Hydroxystearate is about 2% (weight percentage) (see paragraph 00339).
Eva is a review of excipients used in biotechnology products and as such represents the common general knowledge. In section 4.3.6 "Surfactants", it is explained that surfactants are routinely added to protein solutions. According to p. 176, par. 2, polysorbates 20 and 80 (Tween 20 and 80, non ionic surfactants, which PEG15 hydroxystearate is also). Tween 20 was also used in the examples of the present application. Eva teaches non-ionic surfactants have been widely used to reduce protein adsorption on solid surfaces.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical with one of these surfactants and in particular, PEG15 hydroxystearate.
It would have been before the effective filing date of the claimed invention to include a nonionic surfactant (such as PEG15 hydroxystearate), to the composition of Nock. On of ordinary skill in the art would have been motivated to do so given they would improve solubility, stability and are routinely used in pharmaceutical formulations for those purposes. There is a reasonable expectation of success given both of these surfactants are routinely added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage.
Under the principles of KSR v. Teleflex, a combination of known elements is obvious if the skill artisan would have had a reasonable expectation of success, even if the refences do not explicitly states the combination for the same specific use. Nevertheless, PEG15HS and other similar non-ionic surfactants are known to solubilize poorly soluble peptides, prevent adsorption to surfaces an stabilize formulations. These are the same challenges encountered with radiolabeled GRPR antagonists.
Regarding the concentrations found in instant claims 27-28, Alargova teaches concentrations within these ranges. Nevertheless, it would have been obvious to optimize the amount of nonionic surfactant to achieve optimal stability and therapeutic effectiveness.
Response to Applicant’s Arguments
Applicant argues “Applicant has amended claim 15 to specify that the compound of formula (I) is present in a concentration providing a volumetric radioactivity of at least 100 MBq/mL. Applicant has discovered unexpected advantages of using polyethylene glycol 15- hydroxystearate to prevent solid adsorption of compound (I) to solid surfaces (see instant specification Table 1) and also suitable to maintain radiochemical purity (see instant specification Table 2). Radioactive compounds have unique properties due to the need to remain protected against damage from their own radioactivity, and any compounds used in their formulations must satisfy that need. Nock discloses the compound of formula (I) but is silent regarding polyethylene glycol 15-hydroxystearate, and does not teach the adsorption issue.
Eva does not remedy the defects of Nock, as it does not teach the use of polyethylene glycol 15-hydroxystearate, nor does it teach use or specific choices of surfactants compatible with radioactive compounds generally, let alone compound of formula (I) in a concentration providing a volumetric radioactivity of at least 100 MBq/mL. Alargova does not remedy the defects of Nock and Eva, as it teaches use of polyethylene glycol 15-hydroxystearate for a different compound and different issue (namely solubilizing and stabilizing), and does not teach use or specific choices of surfactants compatible with radioactive compounds generally, let alone compound of formula (I) in a concentration providing a volumetric radioactivity of at least 100 MBq/mL. The office action also questions whether the peptide adhesion of Kolliphor HS15 is "unexpected and unobvious and of both statistical and practical significance." Applicant notes that the concentration and radioactivity levels of radiopharmaceuticals are particularly important, in one aspect because adhesion of radiopharmaceuticals to equipment surfaces means additional radioactivity in the equipment which will go into the waste stream. Applicant also points out that going from 6.2% adhesion (Kolliphor HS15) to 7.8% adhesion (EtOH) is an increase of over 25%, which would mean at least 25% more radioactivity in the waste. Thus the difference is in fact significant. Based on the above amendments and argument, Applicant requests withdrawal of the rejections under 35 USC § 103, and allowance of the claims. Further, if the elected composition claims are found allowable, Applicant requests rejoinder of the unelected method claims.
Applicant’s arguments have been fully considered but not found persuasive. The Examiner disagrees that it is unexpected that PEG15-hydroxystearate would prevent adsorption to surfaces. In particular, it is well known that Non-ionic PEG based surfactants (like PEG15-hydroxystearate) are textbook additives for blocking protein/peptide adsorption to glass, metal or plastic surfaces (see Both Eva and Alargova). They adsorb at interface and create a hydrate, steric barrier that prevents adsorption. Pharmaceutical formulations routinely include PEG surfactants precisely to minimize loss of active ingredient through container or filter binding (see both Eva and Alargova). Because the mechanism (surface coating, steric repulsion) and its application to peptides/proteins has long been established, a person of ordinary skill in the art would have had every reason to expect PEG-15 hydroxysterate to reduce radioligand adsorption just as it does for other biologics. The anti-adsorption effect of PEG-15 hydroxystearate in a radiolabeled GRPR-antagonist formulation would have been a routine, predictable outcome of using a known non-surfactant, and thus offers no unexpected technical effect for patentability.
Furthermore, the Examiner notes that the Applicant is claiming unexpected results with regards to use of PEG15-hydrostearate without pointing to specific data or results within the specification or a declaration under 37 C.F.R. 1.132. MPEP716.02 (b) states “The evidence relied upon should establish "that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance." Ex parte Gelles, 22 USPQ2d 1318, 1319 (Bd. Pat. App. & Inter. 1992) (Mere conclusions in appellants’ brief that the claimed polymer had an unexpectedly increased impact strength "are not entitled to the weight of conclusions accompanying the evidence, either in the specification or in a declaration."); Ex parte C, 27 USPQ2d 1492 (Bd. Pat. App. & Inter. 1992) (Applicant alleged unexpected results with regard to the claimed soybean plant, however there was no basis for judging the practical significance of data with regard to maturity date, flowering date, flower color, or height of the plant.). See also In re Nolan, 553 F.2d 1261, 1267, 193 USPQ 641, 645 (CCPA 1977) and In re Eli Lilly, 902 F.2d 943, 14 USPQ2d 1741 (Fed. Cir. 1990) as discussed in MPEP § 716.02(c).” Furthermore, "[A]ppellants have the burden of explaining the data in any declaration they proffer as evidence of non-obviousness." Ex parte Ishizaka, 24 USPQ2d 1621, 1624 (Bd. Pat. App. & Inter. 1992).” In the instant case, Applicants show that Kolliphor HS15 appears to have a 6% peptide adhesion (see Table 1) which is similar to other agents/excipients such as ethanol, albumin, tween. However, there is nothing that shows “that the differences in results are in fact unexpected and unobvious and of both statistical and practical significance” as required for determining unexpected results.
Applicant’s arguments that Eva and Alargova fail to explicitly teach the use of PEG15 HS in radiolabeled formulations is not persuasive. The use of PEG-15HS as a non-ionic surfactant and solubilizing/stabilizing agent is well known in the art, particularly in the formulation of injectable peptide and protein based drugs, including those intended for in vivo imaging or therapeutic use. A person of ordinary skill in the art would understand the challenges associated with formulating radiolabeled peptides-such as poor solubility, aggregation and adsorption-are not unique to radioligands and are well within the common problems addressing by surfactants such as PEG-15HS. As such, the general teachings of the secondary references are directly relevant and applicable.
Under the principles of KSR v. Teleflex, a combination of known elements is obvious if the skill artisan would have had a reasonable expectation of success, even if the refences do not explicitly states the combination for the same specific use. Nevertheless, PEG15HS and other similar non-ionic surfactants are known to solubilize poorly soluble peptides, prevent adsorption to surfaces an stabilize formulations. These are the same challenges encountered with radiolabeled GRPR antagonists.
Furthermore, the claims do recite any specific use or functional limitation relating to PEG15 HS. Therefore , the rejection is based solely on the structural combination of elements and not on any particular result or motivation unless its explicitly recited in the claims. Second, the fact that the prior art may include different motivations for using PEG15HS (e.g. solubilizing and stability) does not preclude a finding of obviousness. MPEP 2144 states “The reason or motivation to modify the reference may often suggest what the inventor has done, but for a different purpose or to solve a different problem. It is not necessary that the prior art suggest the combination to achieve the same advantage or result discovered by applicant”.
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.
Claim(s) 15, 18, 25-31 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-18 of copending Application No. 17/754059 (reference application) in view of Eva ("Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231, cited in Applicant’s IDS) and Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims: A pharmaceutical composition comprising a compound of formula I:
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The instant application additionally claims wherein M is selected from 177Lu, 68Ga ( claim 18); wherein the surfactant is for example polyethylene glycol 15-hydroxystearate (Claim 15); radioactivity of 100 MBq/ML to 500 (see claims 24-27); 25-1000ug/mL surfactant (see claims 26-28); infusion solution (claim 31) and aqueous solution (claim 30).
Copending Application No. 17/754059 claims a method comprising administering to the subject a pharmaceutical composition of a radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonist, wherein said pharmaceutical composition comprises - a radiolabeled GRPR-antagonist of the following formula: MC- S -P wherein: M is a radiometal suitable for therapy, and C is a chelator which binds M; S is an optional spacer covalently linked between C and the N-terminal of P; P is a GRP receptor peptide antagonist covalently bound with its N-terminal to C or to S;and, - one or more pharmaceutically acceptable excipients, wherein said subject has been selected for the treatment by positron emitting tomography (PET) / computed tomography (CT) or PET/ magnetic resonance imaging (MRI) with the same GRPR antagonist as defined for the treatment but with 68Ga as radiometal for use as contrast agent” (See claim 1). Copending Application No. 17/754059 claims the identical radiolabeled GRPR antagonist of the instant claims (see claims 2-4), the formulation for infusion (claim 5). Copending Application No. 17/754059 is silent to including a surfactant and the formulation being aqueous. ). Copending Application No. 17/754059 does disclose use of aqueous formulations (see page 22 of the specification).
However, Eva teaches "Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231) discloses that surfactants are typically added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage. They have been shown to stabilize proteins, inhibit and prevent aggregation, and aid in protein refolding. Polysorbates 20 and 80 (Tween 20 and Tween 80, i.e. Surfactants comprising compounds having (i) a polyethylene glycol chain and (ii) a fatty acid ester) are the most commonly used nonionic surfactant excipients. They are widely reported to inhibit aggregation during stirring, shaking, freeze drying and freeze thawing and can significantly reduce protein adsorption on solid surfaces (see Lee et al., and references therein [118]). (See page 173 second paragraph, page 176 second paragraph). As can be seen, Eva discloses that surfactants such as Tween 20 and Tween 80 can reduce the adsorption of solid surfaces of proteins and, therefore, one skilled in the art can add them to compositions of radiolabeled GRPR-antagonists to reduce their adhesion depending on practical research purposes.
Regarding the specific surfactant of instant claims 19-23, Alargova teaches that “Commonly used parenteral surfactant excipients such as Polysorbate 80 (Tween 80) and Polyoxyl 15 Hydroxystearate (solutol, Kolliphor HS 15) were evaluated to re-assemble and stabilize Conjugate 57 into organized micelles” (See paragraph 00334). Alargova teaches that “he formulation with Solutol showed slightly better PK properties compared to Tween” and improved stability of the conjugate (see paragraph 00339). Alargova additionally teaches “Polyoxyl 15 Hydroxystearate provided great stability to Conjugate 57 and was therefore chosen as a stabilizing and solubilizing excipient. Polyoxyl 15 Hydroxystearate is a water soluble non-ionic surfactant that is typically used in the formulations of pharmaceutical drugs which are poorly water soluble or to stabilize drugs. The concentration of Polyoxyl 15 Hydroxystearate used in the Conjugate 57 solution is between 1% to 10%, between 1% to 5%, or between 2% to 5% (weight percentage). In some embodiments, the concentration of Polyoxyl 15 Hydroxystearate is about 2% (weight percentage) (see paragraph 00339).
Eva is a review of excipients used in biotechnology products and as such represents the common general knowledge. In section 4.3.6 "Surfactants", it is explained that surfactants are routinely added to protein solutions. According to p. 176, par. 2, polysorbates 20 and 80 (Tween 20 and 80) which meet the structural requirements for the surfactant according to present claim 1 (Tween 20 was also used in the examples of the present application) are the most commonly used nonionic surfactant excipients.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical with one of these surfactants.
It would have been before the effective filing date of the claimed invention to include a nonionic surfactant (such as Polyoxyl 15 Hydroxystearate or TWEEN20, which meet the limitations of instant claims 19-23) with water to the composition of US Copending AN 17/754059. On of ordinary skill in the art would have been motivated to do so given they would improve solubility, stability and are routinely used in pharmaceutical formulations for those purposes. There is a reasonable expectation of success given both of these surfactants are routinely added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage
Regarding the concentrations found in instant claims 27-28, Alargova teaches concentrations within these ranges. Nevertheless, it would have been obvious to optimize the amount of nonionic surfactant to achieve optimal stability and therapeutic effectiveness.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants request that the rejections on the grounds of non-statutory double patenting be held in abeyance until finding of otherwise allowable subject matter. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-15 of copending Application No. 17/753762 (reference application) in view of Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims: A pharmaceutical composition comprising a compound of formula I:
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The instant application additionally claims wherein M is selected from 177Lu, 68Ga ( claim 18); wherein the surfactant is for example polyethylene glycol 15-hydroxystearate (Claim 15); radioactivity of 100 MBq/ML to 500 (see claims 24-27); 25-1000ug/mL surfactant (see claims 26-28); infusion solution (claim 31) and aqueous solution (claim 30).
Copending Application No. 17/753762 claims A pharmaceutical composition comprising: (a) a complex formed by (ai) a radionuclide, and (aii) a gastrin-releasing peptide receptor peptide antagonist binding moiety linked to a chelating agent; and; (b) at least two stabilizers against radiolytic degradation; and (c) optionally a surfactant” (claim 1). Copending Application No. 17/753762 further claims NeoB of formula I (claim 5) which is identical to the radiolabeled GRPR antagonist of instant claim 15; 177Lu as the radiolabel (claim 15); Macrogol 15 hydroxystearate as the surfactant (see claim 15).
Regarding the concentrations of the surfactant, Alargova teaches that “Commonly used parenteral surfactant excipients such as Polysorbate 80 (Tween 80) and Polyoxyl 15 Hydroxystearate (solutol, Kolliphor HS 15) were evaluated to re-assemble and stabilize Conjugate 57 into organized micelles” (See paragraph 00334). Alargova teaches that “he formulation with Solutol showed slightly better PK properties compared to Tween” and improved stability of the conjugate (see paragraph 00339). Alargova additionally teaches “Polyoxyl 15 Hydroxystearate provided great stability to Conjugate 57 and was therefore chosen as a stabilizing and solubilizing excipient. Polyoxyl 15 Hydroxystearate is a water soluble non-ionic surfactant that is typically used in the formulations of pharmaceutical drugs which are poorly water soluble or to stabilize drugs. The concentration of Polyoxyl 15 Hydroxystearate used in the Conjugate 57 solution is between 1% to 10%, between 1% to 5%, or between 2% to 5% (weight percentage). In some embodiments, the concentration of Polyoxyl 15 Hydroxystearate is about 2% (weight percentage) (see paragraph 00339).
Regarding the concentrations found in instant claims 27-28, Alargova teaches concentrations within these ranges. Nevertheless, it would have been obvious to optimize the amount of nonionic surfactant to achieve optimal stability and therapeutic effectiveness. Regarding the radioactivity, this is also a result effective variable and it should be optimize to achieve optimal labeling and therapeutic effectiveness.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants request that the rejections on the grounds of non-statutory double patenting be held in abeyance until finding of otherwise allowable subject matter. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-8, 10-18 of co-pending Application No. 17/753850 (reference application) in view of Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims: A pharmaceutical composition comprising a compound of formula I:
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The instant application additionally claims wherein M is selected from 177Lu, 68Ga ( claim 18); wherein the surfactant is for example polyethylene glycol 15-hydroxystearate (Claim 15); radioactivity of 100 MBq/ML to 500 (see claims 24-27); 25-1000ug/mL surfactant (see claims 26-28); infusion solution (claim 31) and aqueous solution (claim 30).
Copending Application No. 17753850 A method for labeling a gastrin-releasing peptide receptor (GRPR) antagonist with a radioactive isotope, said method comprising the steps of: i. providing a first vial comprising said GRPR antagonist in dried form, ii. adding a solution of said radioactive isotope into said first vial, thereby obtaining a solution of said GRPR antagonist with said radioactive isotope, iii. mixing the solution obtained in ii. with at least a buffering agent and incubating it for a sufficient period of time for obtaining said GRPR antagonist labeled with said radioactive isotope, and, iv. optionally, adjusting the pH of the solution” (See claim 1). Co-pending Application No. 17753850 further claims the identical radiolabeled GRPR antagonist (see claim 4) of instant claim 15; macrogol 15 hydroxystearate (Fatty acid PEG) (see claim 8, 18); radioactive isotope of 68Ga (see claim 10). Copending Application No. 17753850 teaches different amounts of surfactant and isotope but does not claim specific concentrations.
It would have been obvious to optimize the amount of nonionic surfactant/radioisotope to achieve optimal stability and therapeutic effectiveness and labeling.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to Applicant’s Arguments
Applicants request that the rejections on the grounds of non-statutory double patenting be held in abeyance until finding of otherwise allowable subject matter. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11083805 B2. Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims: A pharmaceutical composition comprising a compound of formula I:
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The instant application additionally claims wherein M is selected from 177Lu, 68Ga ( claim 18); wherein the surfactant is for example polyethylene glycol 15-hydroxystearate (Claim 15); radioactivity of 100 MBq/ML to 500 (see claims 24-27); 25-1000ug/mL surfactant (see claims 26-28); infusion solution (claim 31) and aqueous solution (claim 30).
US Patent No. ‘805 claims “A method of diagnosing primary and/or metastatic GRPR-positive cancer, the method comprising administering an effective amount of a radiolabeled GRPR-antagonist to a subject, wherein said radiolabeled GRPR-antagonist is of general formula MC—S—P wherein:
M is a radiometal and C is a metal chelator that binds M, or MC is a Tyr- or prosthetic group bound to a radiohalogen, and S is a spacer covalently linked between C and P, wherein S is covalently attached to the N-terminus of P; and P is DPhe-Gln-Trp-Ala-Val-Gly-His-NH—CH[CH2—CH(CH3)2]2 (SEQ ID NO:1), thereby imaging said subject” (see claim 1). US Patent No. ‘805 further claims wherein M is 68Ga, 177Lu (see claim 4); DOTA-chelator (see claim 6). The compound of instant claim 15 is encompassed by claims 1-17 of US Patent No. ‘805. US Patent No. ‘805 is silent to including a surfactant and the formulation being aqueous and concentrations thereof).
However, Eva teaches "Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231) discloses that surfactants are typically added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage. They have been shown to stabilize proteins, inhibit and prevent aggregation, and aid in protein refolding. Polysorbates 20 and 80 (Tween 20 and Tween 80, i.e. Surfactants comprising compounds having (i) a polyethylene glycol chain and (ii) a fatty acid ester) are the most commonly used nonionic surfactant excipients. They are widely reported to inhibit aggregation during stirring, shaking, freeze drying and freeze thawing and can significantly reduce protein adsorption on solid surfaces (see Lee et al., and references therein [118]). (See page 173 second paragraph, page 176 second paragraph). As can be seen, Eva discloses that surfactants such as Tween 20 and Tween 80 can reduce the adsorption of solid surfaces of proteins and, therefore, one skilled in the art can add them to compositions of radiolabeled GRPR-antagonists to reduce their adhesion depending on practical research purposes.
Regarding the specific surfactant of instant claims 19-23, Alargova teaches that “Commonly used parenteral surfactant excipients such as Polysorbate 80 (Tween 80) and Polyoxyl 15 Hydroxystearate (solutol, Kolliphor HS 15) were evaluated to re-assemble and stabilize Conjugate 57 into organized micelles” (See paragraph 00334). Alargova teaches that “he formulation with Solutol showed slightly better PK properties compared to Tween” and improved stability of the conjugate (see paragraph 00339). Alargova additionally teaches “Polyoxyl 15 Hydroxystearate provided great stability to Conjugate 57 and was therefore chosen as a stabilizing and solubilizing excipient. Polyoxyl 15 Hydroxystearate is a water soluble non-ionic surfactant that is typically used in the formulations of pharmaceutical drugs which are poorly water soluble or to stabilize drugs. The concentration of Polyoxyl 15 Hydroxystearate used in the Conjugate 57 solution is between 1% to 10%, between 1% to 5%, or between 2% to 5% (weight percentage). In some embodiments, the concentration of Polyoxyl 15 Hydroxystearate is about 2% (weight percentage) (see paragraph 00339).
Eva is a review of excipients used in biotechnology products and as such represents the common general knowledge. In section 4.3.6 "Surfactants", it is explained that surfactants are routinely added to protein solutions. According to p. 176, par. 2, polysorbates 20 and 80 (Tween 20 and 80) which meet the structural requirements for the surfactant according to present claim 1 (Tween 20 was also used in the examples of the present application) are the most commonly used nonionic surfactant excipients.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical with one of these surfactants.
It would have been before the effective filing date of the claimed invention to include a nonionic surfactant (such as Polyoxyl 15 Hydroxystearate or TWEEN20, which meet the limitations of instant claims 19-23) with water to the composition of US Patent NO. ‘805. On of ordinary skill in the art would have been motivated to do so given they would improve solubility, stability and are routinely used in pharmaceutical formulations for those purposes. There is a reasonable expectation of success given both of these surfactants are routinely added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage
Regarding the concentrations found in instant claims 27-28, Alargova teaches concentrations within these ranges. Nevertheless, it would have been obvious to optimize the amount of nonionic surfactant and radioactivity to achieve optimal stability, labeling and therapeutic effectiveness.
Response to Applicant’s Arguments
Applicants request that the rejections on the grounds of non-statutory double patenting be held in abeyance until finding of otherwise allowable subject matter. Thus, the rejection is maintained.
New Objection
Claim 25 is objected to for the following informality: Claim 25 appears to be missing the end of the claim and the period. Claim 25 should be amended to recite “250 MBq/mL and 500 MBq/mL.”
New Rejections
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.
Claim(s) 15, 18, 25-31 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 16-45 of co-pending Application No. 19/234864 (reference application) in view of Eva ("Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231, cited in Applicant’s IDS) and Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously).
Although the claims at issue are not identical, they are not patentably distinct from each other because:
The instant application claims: A pharmaceutical composition comprising a compound of formula I:
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The instant application additionally claims wherein M is selected from 177Lu, 68Ga ( claim 18); wherein the surfactant is for example polyethylene glycol 15-hydroxystearate (Claim 15); radioactivity of 100 MBq/ML to 500 (see claims 24-27); 25-1000ug/mL surfactant (see claims 26-28); infusion solution (claim 31) and aqueous solution (claim 30).
Co-pending Application 19/234864 claims “Aprocess for manufacturing a pharmaceutical aqueous solution, the process comprising diluting an aqueous complex solution with an aqueous dilution solution to form the pharmaceutical aqueous solution; wherein the aqueous complex solution comprises: (a) a complex comprising (ai) the radionuclide 177Lu (Lutetium-177) and (aii) a cell receptor binding organic moiety linked to a chelating agent, and (b) at least one stabilizer(s) against radiolytic degradation that is/are present in an amount to result in a concentration of at least 1 mg/mL in the pharmaceutical aqueous solution; and wherein the aqueous dilution solution comprises at least one stabilizer(s) against radiolytic degradation present in an amount to result in a concentration of at least 15 mg/mL in the pharmaceutical aqueous solution; wherein the radionuclide is present in the pharmaceutical aqueous solution in a concentration that provides a volumetric radioactivity of at least 370 MBq/mL; and the pharmaceutical aqueous solution comprises less than 5% ethanol by weight” (Claim 16). Co-pending Application 19/234864 further claims wherein the cell receptor binding moiety linked to a chelating agent is NeoB of formula I (see clam 26) which is identical to instant claim 15; and an MBq/ml of at least 370 (see claim 16); 177Lu (claim 16); aqueous solution (claim 16); a stabilizer (claim 34); and a solution (claim 38).
Co-pending Application 19/234864 is silent to including a surfactant and concentrations thereof.
However, Eva teaches "Pharmaceutical Excipients: Properties, Functionality, and Applications in Research and Industry", pages 145-198, publication date: 20171231) discloses that surfactants are typically added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage. They have been shown to stabilize proteins, inhibit and prevent aggregation, and aid in protein refolding. Polysorbates 20 and 80 (Tween 20 and Tween 80, i.e. Surfactants comprising compounds having (i) a polyethylene glycol chain and (ii) a fatty acid ester) are the most commonly used nonionic surfactant excipients. They are widely reported to inhibit aggregation during stirring, shaking, freeze drying and freeze thawing and can significantly reduce protein adsorption on solid surfaces (see Lee et al., and references therein [118]). (See page 173 second paragraph, page 176 second paragraph). As can be seen, Eva discloses that surfactants such as Tween 20 and Tween 80 can reduce the adsorption of solid surfaces of proteins and, therefore, one skilled in the art can add them to compositions of radiolabeled GRPR-antagonists to reduce their adhesion depending on practical research purposes.
Regarding the specific surfactant of instant claim 15 (PEG 15-hydroxystearate), Alargova teaches that “Commonly used parenteral surfactant excipients such as Polysorbate 80 (Tween 80) and Polyoxyl 15 Hydroxystearate (solutol, Kolliphor HS 15) were evaluated to re-assemble and stabilize Conjugate 57 into organized micelles” (See paragraph 00334). Alargova teaches that “the formulation with Solutol showed slightly better PK properties compared to Tween” and improved stability of the conjugate (see paragraph 00339). Alargova additionally teaches “Polyoxyl 15 Hydroxystearate provided great stability to Conjugate 57 and was therefore chosen as a stabilizing and solubilizing excipient. Polyoxyl 15 Hydroxystearate is a water soluble non-ionic surfactant that is typically used in the formulations of pharmaceutical drugs which are poorly water soluble or to stabilize drugs. The concentration of Polyoxyl 15 Hydroxystearate used in the Conjugate 57 solution is between 1% to 10%, between 1% to 5%, or between 2% to 5% (weight percentage). In some embodiments, the concentration of Polyoxyl 15 Hydroxystearate is about 2% (weight percentage) (see paragraph 00339).
Eva is a review of excipients used in biotechnology products and as such represents the common general knowledge. In section 4.3.6 "Surfactants", it is explained that surfactants are routinely added to protein solutions. According to p. 176, par. 2, polysorbates 20 and 80 (Tween 20 and 80) which meet the structural requirements for the surfactant according to present claim 1 (Tween 20 was also used in the examples of the present application) are the most commonly used nonionic surfactant excipients.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical with one of these surfactants.
It would have been before the effective filing date of the claimed invention to include a nonionic surfactant (such as Polyoxyl 15 Hydroxystearate or TWEEN20, which meet the limitations of instant claim 15) with water to the composition of Co-pending Application 19/234864. On of ordinary skill in the art would have been motivated to do so given they would improve solubility, stability and are routinely used in pharmaceutical formulations for those purposes. There is a reasonable expectation of success given both of these surfactants are routinely added to protein solutions to prevent physical damage during purification, filtration, transport, freeze drying, spray drying and storage
Regarding the concentrations found in instant claims 15, 27-28, Alargova teaches concentrations within these ranges. Nevertheless, it would