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
The amendment after non-final office action filed January 28, 2026 is acknowledged. Claims 1-14, 16-17, 19-24 were cancelled, claim 15 was amended, Claim 36 was newly added and claims 15, 18, 25-36 are pending.
*After further review, a second Non-final follows.
Election/Restrictions
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 Claims 32-35 remain withdrawn from consideration as being drawn to a non-elected invention.
Claims 15, 18, 25-31 and 36 are examined on the merits in this office action.
Withdrawn Objections/Rejections
The rejection of claim(s) 15, 18, 25-31 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publication date: 20171231, cited in Applicant’s IDS) and Alargova (WO2018081521 A1, 10/27/2017 priority date) is withdrawn in view of amendment of the claims filed January 28, 2026 and additional art addressing the concentration range found in instant claim 28.
The rejection of claim(s) 15, 18, 25-31, 36 on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-18 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date: 20171231, cited in Applicant’s IDS) and Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously) is withdrawn in view of amendment of the claims filed January 28, 2026.
The rejection of claim(s) 15, 18, 25-31 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17/753762 (reference application) in view of Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously) is withdrawn in view of amendment of the claims filed January 28, 2026.
The rejection of claim(s) 15, 18, 25-31 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) is withdrawn in view of amendment of the claims filed January 28, 2026.
The rejection of claim(s) 15, 18, 25-31 on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11083805 B2 is withdrawn in view of amendment of the claims filed January 28, 2026.
The rejection of claim(s) 15, 18, 25-31 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) is withdrawn in view of amendment of the claims filed January 28, 2026.
New Objection
Claim 18 is objected to for the following informality: the limitation of “177Lu, 68Ga” should be replaced with -177Lu[[,]]and 68Ga-.
Claim 25 is objected to for the following informality: claim 25 should be amended as follows: The pharmaceutical composition according to claim 15, wherein the compound of formula (I) is present in a concentration providing a volumetric radioactivity of between 250 MBq/mL and 500 MBq/mL.
Claim 36 is objected to for the following informality: claim 36 is missing a period and thus should be amended to include a period. See MPEP 608.01(m).
New 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 and 36 are rejected under 35 U.S.C. 103 as being unpatentable over Nock (US20150265732 A1, cited previously) in view of Dalm (J. Nucl. Med. 2017, 58:293-299), 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) and Gonzalez (Biopharmaceutics and Drug disposition, 25:37-49 (2004)).
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).
However, Dalm teaches closely related radiolabeled GRPR antagonists (e.g. NeoBOMB1) and discloses that a surface active agent may be added to prevent sticking of the peptide prior to administration (see Materials and Methods). Thus, Dalm provides explicit motivation to include a surfactant in radiolabeled GRPR antagonist compositions to reduce adhesion to surfaces.
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. Accordingly, Eva supports the use of surfactants to reduce adsorption of peptide based compositions to surfaces such as glass or plastic.
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).
Gonzalez teaches use of Solutol HS15 (PEG-15 hydroxystearate) at concentrations of 0.003%, 0.03% and 0.3% (w/v), corresponding to approximately 30, 300 and 3000 ug/mL, respectively (see abstract). Gonzalez demonstrates that such surfactants exhibit functional effects in a dose dependent manner, including at low concentrations overlapping the claimed range of instant claim 28 (see abstract). Thus, Gonzalez evidences PEG15-HS is effective across a range of concentrations, including low concentrations, and supports that selected an appropriate concentration would have been within the routine skill of the art.
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 of Nock with a surfactant as taught by Dalm to prevent sticking of the peptide. Eva provides that nonionic surfactants reduce adsorption to surfaces and Algarova teaches that PEG15 hydroxystearate as a suitable surfactant for stabilizing peptide conjugates. Gonzalez further demonstrates that such surfactants are effective across a range of concentrations including low concentrations that overlap the instant claims.
Therefore, 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. In view of Dalm’s teaching to add a surfactant to prevent peptide sticking, together with Eva’s disclosure that nonionic surfactants reduce surface adsorption and Alargova’s teaching of PEG15 hydroxystearate for stabilizing peptide formulations, further supported by Gonzalez’s demonstration of effectiveness across a range of concentrations, one of ordinary skill in the art would have had a reasonable expectation of success in including PEG15 hydroxystearate in the composition of Nock to reduce adhesion and act as an effective non-ionic surfactant excipient.
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 26-27, Alargova teaches concentrations within these ranges. Gonzalez demonstrates that such surfactants exhibit functional effects in a dose dependent manner, including at low concentrations overlapping the claimed range of instant claim 28.
Nevertheless, it would have been obvious to optimize the amount of nonionic surfactant to achieve optimal stability and therapeutic effectiveness.
Regarding claim 36, Nock teaches radiolabeled composition having volumetric radio activities that overlap with or exceed the claimed “at least 100 Mba/mL”. For example, Nock discloses concentrations corresponding to at least 100 MBq/ml (see paragraphs 0094-0095). It is well established that where the claimed range overlaps with or lies within a range disclosed in the prior art, a prima facie case of obviousness exists. Therefore, it would have been obvious to select a radioactivity of at least 100 MBq/mL as claimed.
Regarding the limitation of “formula (I) shows reduced adhesion to glass and plastic surfaces” (instant claim 15), this an inherent property of the combination of the PEG15-HS and formula I. The combined references teaches the same combination with the same concentrations and thus, this property is inherent to the combination.
Response to Applicant’s Arguments
Applicant argues that “Applicant has amended claim 15 to require the feature "wherein the compound of formula (I) shows reduced adhesion to glass and plastic surfaces." As noted previously, Nock does not disclose that the compound of formula (I) has issues with adhesion to glass or plastic surfaces, nor does it suggest any remedy for that issue. Eva and Alargova, although they disclose surfactants, do not teach the adhesion issue for the compound of formula (I), nor do they teach that polyethylene glycol 15 hydroxystearate would show unexpected benefit for reduction of adhesion of that compound, as shown in the present application (see Table 1). Further, applicant notes that the radioactivity levels that are the basis of the % adhesion results in Table 1 are measured with considerable accuracy and precision, and that the results are statistically significant. Applicant further notes that adhesion depends on the overall structure of the compound, that the compound of formula (I) is dominated by its peptide and non- peptide domains, and that the nature of the radiometal would not be expected to affect the adhesion. Thus Applicant submits that the effect of the reduced adhesion would be expected to be applicable for the full set of radiometals. Based on the above amendments and argument, Applicant submits that claim 15 is novel and unobvious over the cited art. As the remaining claims depend directly or indirectly from claim 15, the remaining claims are also novel and unobvious. Applicant therefore requests withdrawal of the rejections under 35 USC § 103. As withdrawn claims 32-35 depend directly or indirectly from claim 15, applicant requests rejoinder of these claims once the elected claims are found allowable.
Applicant’s arguments have been fully considered but not found persuasive. While Nock does not explicitly describe adhesion to glass or plastic surfaces, Eva expressly teaches that proteins and peptides adsorb to solid surfaces and that surfactants are routinely used to reduce such adsorption. Furthermore, Dalm teaches adding tensioactive agents (surfactants) to radiolabeled GRPR antagonists to prevent sticking prior to administration.
In response to Applicant’s arguments that the art does not teach PEG15-HS for this purpose, the Examiner respectfully disagrees. Eva teaches nonionic surfactants (including PEG based surfactants) reduce adsorption. Alargova explicitly teaches PEG15-HS as a stabilizing surfactant in peptide conjugates and Gonzales teaches such surfactants, including PEG15-HS, are effective across a range of concentrations with regard to being a surface-active excipient. Furthermore, as stated above, 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. In view of Dalm’s teaching to add a surfactant to prevent peptide sticking, together with Eva’s disclosure that nonionic surfactants reduce surface adsorption and Alargova’s teaching of PEG15 hydroxystearate for stabilizing peptide formulations, further supported by Gonzalez demonstration of effectiveness across a range of concentrations, one of ordinary skill in the art would have had a reasonable expectation of success in including PEG15 hydroxystearate in the composition of Nock to reduce adhesion and act as an effective non-ionic surfactant excipient. Nevertheless, it is well established that the rationale to combine references need not be identical to that of the Applicant. Rather, it is sufficient that the prior art provide a reason that would have prompted a person of ordinary skill in the art to make the combination. In the instant case, 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.
With regards to Applicant’s arguments that the data demonstrate that PEG15-HS reduces adhesion and this is an unexpected result, the Examiner respectfully disagrees.
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. The data confirms that the effect is not unique to PEG15-HS, as other non-ionic surfactants show reduced adhesion, and the result is consistent with general knowledge in the art with regards to properties of these surfactants.
Regarding Table 2, Applicants show that adhesion with Kolliphor HS15 (0.5 mg) was 4.2% at the whereas Tween 20 is 5.2% at the highest amount. This difference is very small in magnitude and appears to comparable to other surfactants and within a range expected for similar surfactants. There does not appear to be a statistically significant superior result compared to other surfactants with similar properties. Applicant’s data in Table 2 does not establish that the observed differences between Kolliphor HS15 and other surfactants are statistically significant. While minor differences in adhesion are reported, no information is provided regarding variability, error margins, or statistical analysis. As such, it is unclear whether the observed differences represent true improvement or fall within experimental variation.
MPEP 716.02(b) states that “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, claim 15 does not recite any limitation on the amount of surfactant. As such, the claim encompasses any concentration. Applicant’s data, which is limited to specific amounts, is therefore not commensurate in scope with the claim. Moreover, the selection of suitable surfactant concentration is considered a result effective variable subject to routine optimization.
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, 36 are/remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-5, 7-18 of copending Application No. 17/754059 (reference application) in view of in view of Dalm (J. Nucl. Med. 2017, 58:293-299), 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) and Gonzalez (Biopharmaceutics and Drug disposition, 25:37-49 (2004))..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) and radioactivity of at least 100 MBq/ML (claim 36).
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 (PEG15-HS) and amounts thereof and the formulation being aqueous. Co-pending Application No. 17/754059 does disclose use of aqueous formulations (see page 22 of the specification).
However, Dalm teaches closely related radiolabeled GRPR antagonists (e.g. NeoBOMB1) and discloses that a surface active agent may be added to prevent sticking of the peptide prior to administration (see Materials and Methods). Thus, Dalm provides explicit motivation to include a surfactant in radiolabeled GRPR antagonist compositions to reduce adhesion to surfaces.
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. Accordingly, Eva supports the use of surfactants to reduce adsorption of peptide based compositions to surfaces such as glass or plastic.
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).
Gonzalez teaches use of Solutol HS15 (PEG-15 hydroxystearate) at concentrations of 0.003%, 0.03% and 0.3% (w/v), corresponding to approximately 30, 300 and 3000 ug/mL, respectively (see abstract). Gonzalez demonstrates that such surfactants exhibit functional effects in a dose dependent manner, including at low concentrations overlapping the claimed range of instant claim 28 (see abstract). Thus, Gonzalez evidences PEG15-HS is effective across a range of concentrations, including low concentrations, and supports that selected an appropriate concentration would have been within the routine skill of the art.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical of Co-pending Application No. 17/754059 with a surfactant as taught by Dalm to prevent sticking of the peptide. Eva provides that nonionic surfactants reduce adsorption to surfaces and Algarova teaches that PEG15 hydroxystearate as a suitable surfactant for stabilizing peptide conjugates. Gonzalez further demonstrates that such surfactants are effective across a range of concentrations including low concentrations that overlap the instant claims.
Therefore, 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 Co-pending Application No. 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. In view of Dalm’s teaching to add a surfactant to prevent peptide sticking, together with Eva’s disclosure that nonioninc surfactants reduce surface adsorption and Alargova’s teaching of PEG15 hydroxystearate for stabilizing peptide formulations, further supported by Gonzalez’s demonstration of effectiveness across a range of concentrations, one of ordinary skill in the art would have had a reasonable expectation of success in including PEG15 hydroxystearate in the composition of Co-pending Application No. 17/754059 to reduce adhesion and act as an effective non-ionic surfactant excipient.
Regarding the concentrations found in instant claims 26-28, Alargova and Gonzalez 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 do no address the rejection over co-pending Application No. 17/754059. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31, 36 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 3, 9-15 of co-pending Application No. 17/753762 (reference application) in view of Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously) Gonzalez (Biopharmaceutics and Drug disposition, 25:37-49 (2004)).
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) and radioactivity of at least 100 MBq/ML (claim 36).
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).
Gonzalez teaches use of Solutol HS15 (PEG-15 hydroxystearate) at concentrations of 0.003%, 0.03% and 0.3% (w/v), corresponding to approximately 30, 300 and 3000 ug/mL, respectively (see abstract). Gonzalez demonstrates that such surfactants exhibit functional effects in a dose dependent manner, including at low concentrations overlapping the claimed range of instant claim 28 (see abstract). Thus, Gonzalez evidences PEG15-HS is effective across a range of concentrations, including low concentrations, and supports that selected an appropriate concentration would have been within the routine skill of the art.
Regarding the concentrations found in instant claims 26-28, Alargova and Gonzalez 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 do no address the rejection over co-pending Application No. 17/753762. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31, 36 remain provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-7, 10, 18 of co-pending Application No. 17/753850 (reference application) in view of Alargova (WO2018081521 A1, 10/27/2017 priority date, cited previously) Gonzalez (Biopharmaceutics and Drug disposition, 25:37-49 (2004)).
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) and radioactivity of at least 100 MBq/ML (claim 36).
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 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.
The teachings of Alargova and Gonzalez are provided in the above rejections.
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 do no address the rejection over Copending Application No. 17753850. Thus, the rejection is maintained.
Claim(s) 15, 18, 25-31, 369 remain rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-17 of U.S. Patent No. 11083805 B2 in view of Dalm (J. Nucl. Med. 2017, 58:293-299), 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) and Gonzalez (Biopharmaceutics and Drug disposition, 25:37-49 (2004)).. 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) and radioactivity of at least 100 MBq/ML (claim 36).
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 (in particular, PEG15-HS) and the formulation being aqueous and concentrations thereof.
However, Dalm teaches closely related radiolabeled GRPR antagonists (e.g. NeoBOMB1) and discloses that a surface active agent may be added to prevent sticking of the peptide prior to administration (see Materials and Methods). Thus, Dalm provides explicit motivation to include a surfactant in radiolabeled GRPR antagonist compositions to reduce adhesion to surfaces.
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. Accordingly, Eva supports the use of surfactants to reduce adsorption of peptide based compositions to surfaces such as glass or plastic.
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).
Gonzalez teaches use of Solutol HS15 (PEG-15 hydroxystearate) at concentrations of 0.003%, 0.03% and 0.3% (w/v), corresponding to approximately 30, 300 and 3000 ug/mL, respectively (see abstract). Gonzalez demonstrates that such surfactants exhibit functional effects in a dose dependent manner, including at low concentrations overlapping the claimed range of instant claim 28 (see abstract). Thus, Gonzalez evidences PEG15-HS is effective across a range of concentrations, including low concentrations, and supports that selected an appropriate concentration would have been within the routine skill of the art.
It was thus obvious to the skilled person that the above-defined problem would be solved by combining the radiopharmaceutical of US Patent NO. ‘805 with a surfactant as taught by Dalm to prevent sticking of the peptide. Eva provides that nonionic surfactants reduce adsorption to surfaces and Algarova teaches that PEG15 hydroxystearate as a suitable surfactant for stabilizing peptide conjugates. Gonzalez further demonstrates that such surfactants are effective across a range of concentrations including low concentrations that overlap the instant claims.
Therefore, 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 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. In view of Dalm’s teaching to add a surfactant to prevent peptide sticking, together with Eva’s disclosure that nonioninc surfactants reduce surface adsorption and Alargova’s teaching of PEG15 hydroxystearate for stabilizing peptide formulations, further supported by Gonzalez’s demonstration of effectiveness across a range of concentrations, one of ordinary skill in the art would have had a reasonable expectation of success in including PEG15 hydroxystearate in the composition of US Patent No. ‘805 to reduce adhesion and act as an effective non-ionic surfactant excipient.
Regarding the concentrations found in instant claims 26-28, Alargova and Gonzalez 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.
Response to Applicant’s Arguments
Applicant notes that there is no mention whatsoever of surfactants in '805, let alone polyethylene glycol 15 hydroxystearate as recited in the present claims. There is also no mention in '805 of the issue of a compound of formula (I) adhering to glass or plastic surfaces, nor any teaching of how to reduce it, which are features of the presently amended claims. Eva discloses surfactants, but does not teach that a compound of formula (I) would adhere to surfaces, nor does it suggest a remedy for that. Alargova does mention polyethylene glycol 15 hydroxystearate, but likewise does not teach that a compound of formula (I) would adhere to surfaces, or that polyethylene glycol 15 hydroxystearate should be used with formulations of compound (I). In particular, none of the cited references provides the expectation that polyethylene glycol 15 hydroxystearate would be superior to other surfactants for the specific purpose of reducing the adhesion of a compound of formula (I) (See instant application Table 1). Based on the lack of recognition in the cited art of an unexpected problem, and an unexpectedly superior result for solution of said problem, there is no logic other than impermissible hindsight analysis, to arrive at the presently amended claims by cherry picking surfactants from the literature and combining them with '805, which again does not teach the adhesion issue and does not even mention surfactants. The present claims are directed to a problem and a solution to that problem, neither of which are disclosed or taught in the cited application, and a person of skill viewing Eva and Alargova would likewise not know of the problem nor its specific solution. Based on the above, Applicant submits that the present claims are patentably distinct from the claims of '805, and requests the withdrawal of the double patenting rejection.
Applicant’s arguments have been fully considered but not found persuasive. The Examiner acknowledges that US Patent No. ‘805 is silent to including a surfactant (in particular, PEG15-HS) and the formulation being aqueous and concentrations thereof.
However, as stated in the above rejection, 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 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. In view of Dalm’s teaching to add a surfactant to prevent peptide sticking, together with Eva’s disclosure that nonioninc surfactants reduce surface adsorption and Alargova’s teaching of PEG15 hydroxystearate for stabilizing peptide formulations, further supported by Gonzalez’s demonstration of effectiveness across a range of concentrations, one of ordinary skill in the art would have had a reasonable expectation of success in including PEG15 hydroxystearate in the composition of US Patent No. ‘805 to reduce adhesion and act as an effective non-ionic surfactant excipient.
Regarding the concentrations found in instant claims 26-28, Alargova and Gonzalez 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.
Regarding Applicants assertions of unexpected results (Tables 1-2), the Examiner respectfully disagrees. 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. The data confirms that the effect is not unique to PEG15-HS, as other non-ionic surfactants show reduced adhesion, and the result is consistent with general knowledge in the art with regards to properties of these surfactants.
Regarding Table 2, Applicants show that adhesion with Kolliphor HS15 (0.5 mg) was 4.2% at the whereas Tween 20 is 5.2% at the highest amount. This difference is very small in magnitude and appears to comparable to other surfactants and within a range expected for similar surfactants. There does not appear to be a statistically significant superior result compared to other surfactants with similar properties. Applicant’s data in Table 2 does not establish that the observed differences between Kolliphor HS15 and other surfactants are statistically significant. While minor differences in adhesion are reported, no information is provided regarding variability, error margins, or statistical analysis. As such, it is unclear whether the observed differences represent true improvement or fall within experimental variation.
MPEP 716.02(b) states that “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).”
Conclusion
No claims are allowed.
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/ERINNE R DABKOWSKI/Examiner, Art Unit 1654
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