DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Status of Claims
Claims 2 and 3 have been amended. Claims 2, 3 and 5 are pending and are examined herein on the merits for patentability.
Response to Arguments
Applicant’s arguments have been fully considered. Any rejection not reiterated herein has been withdrawn. The previous rejection has been modified to address claim amendment. The Examiner’s response to Applicant’s arguments is incorporated below.
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 2, 3 and 5 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claim 14 of copending Application No. 18/169,180 (reference application), for reasons set forth in the previous Office Action. This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Response to arguments
Applicant argues that the pending claims of, including claim 14, are directed to a method of preparing compounds, and not to the instantly claimed compound products, and therefore the claims are patentably distinct.
Applicant’s arguments have been fully considered but are not found to be persuasive. It is respectfully submitted that tne method of application ‘180 necessarily results in the instantly claimed product and accordingly encompass the product of the instant claims, as evidenced by the specification at page 15. Accordingly, the claims are overlapping in scope and are obvious variants of one another.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
Claim(s) 2, 3 and 5 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Engell et al. (WO 2019/185932).
Engell discloses a method for the synthesis of an injectable composition comprising a [18F]-labelled pyridaben derivative that is advantageous over prior methods. In particular, the method of the present invention comprises a method of radiosynthesis that permits a more facile purification using solid phase extraction (SPE) (abstract). The synthesis of an injectable composition comprising the compound [18F]- flurpiridaz ([18F]-FPZ) is described wherein the method comprises nucleophilic [18F]- fluorination of a tosylate precursor compound, dilution with water followed by high- performance liquid chromatography (FIPLC) purification (page 1).
The present inventors identified that the radioimpurity is formed due to radiolysis of [18F]FPZ during the radiolabelling reaction (page 3).
In one embodiment of the invention, said compound of Formula I is:
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wherein LG is as variously defined herein; and said compound of Formula II is:
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.
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Addition of TEMPO to the precursor reduces the radiolysis substantially, e.g. from up to 22% to 1 % at 100 GBa starting activity (pages 10-11). See Examples 1 and 2, wherein in Example 1 the % of [18F]Flurpiridaz in the crude product was 81 % with 13% of a late eluting radiolysis product (Figure 1 ); and in Example 2 the % of [18F]Flurpiridaz in the crude product was 92% with 1 % of the late eluting radiolysis product. The addition of TEMPO to the labelling reaction reduces the amount of the late eluting radiolysis product (Figure 1). The present inventors deduce from these results that even when carried out at high activity the addition of TEMPO to the radiolabelling reaction acts to reduce the late eluting radiolysis product.
Accordingly Engell discloses [18F]Flurpiridaz with 1% radioimpurity (radiolysis product). Regarding the claimed compound represented by
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, the Office does not have the facilities for examining and comparing applicant’s product with the product of the prior art in order to establish that the product of the prior art does not possess the same functional characteristics of the claimed product. In the absence to the contrary, the burden is upon the applicant to prove that the claimed products are functionally different than those taught by the prior art and to establish patentable differences. See Ex parte Phillips, 28 U.S.P.Q.2d 1302, 1303 (PTO Bd. Pat. App. & Int. 1993), Ex parte Gray, 10 USPQ2d 1922, 1923 (PTO Bd. Pat. App. & Int.) and In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977).
The instant specification recites at published paragraph 0042-0046: ...In step F, the compound to be radiolabelled (also referred to herein as the ‘precursor’, or ‘final intermediate’), dissolved in acetonitrile, is added to the reaction vessel. The precursor may for example carry a tosyl group (tosylate) that will be replaced by the 18F- radiolabel. This fluorination step yields the crude product. Subsequently, purification steps are carried out to yield the pure radiolabelled compound (pure drug substance) and, following sterile filtration, the drug product.
[0043] Several experiments were performed to investigate the impact that increasing levels of water in the precursor vial had on the radiolabelling process. [0044] The water content during the radiolabelling reaction in step F was found to be an important variable in the amount of radio-impurity (for example, radiochemical impurity B, depicted below) formed in the crude product. [0045] The structure of radioimpurity B is as (shown). [0046] Experimental results support the hypothesis that radiochemical impurities (for example, radiochemical impurity B) are formed via a free radical radiolysis mechanism. Water is a potential source of free radicals and a high amount of analogue of the hydroxy impurity was observed in the LC-MS analysis of the crude product. Since Engell states that the radioimpurity is formed due to radiolysis of [18F]FPZ during the radiolabelling reaction and the instant specification states that radiochemical impurity B) are formed via a free radical radiolysis mechanism, and both Engell and the instant specification disclose radiosynthesis of [18F]FPZ from the tosylate precursor in acetonitrile solution; absent evidence to the contrary it is interpreted that the radiolysis product/radioimpurity in Engell necessarily results in the same structure as instantly claimed. See also MPEP 2112. There is no requirement that a person of ordinary skill in the art would have recognized the inherent disclosure at the relevant time, but only that the subject matter is in fact inherent in the prior art reference. Schering Corp. v. Geneva Pharm. Inc., 339 F.3d 1373, 1377, 67 USPQ2d 1664, 1668 (Fed. Cir. 2003) (rejecting the contention that inherent anticipation requires recognition by a person of ordinary skill in the art before the critical date and allowing expert testimony with respect to post-critical date clinical trials to show inherency); see also Toro Co. v. Deere & Co., 355 F.3d 1313, 1320, 69 USPQ2d 1584, 1590 (Fed. Cir. 2004) ("[T]he fact that a characteristic is a necessary feature or result of a prior-art embodiment (that is itself sufficiently described and enabled) is enough for inherent anticipation, even if that fact was unknown at the time of the prior invention."); Abbott Labs v. Geneva Pharms., Inc., 182 F.3d 1315, 1319, 51 USPQ2d 1307, 1310 (Fed.
With regard to the amended limitation wherein the impurity compound is present in an amount between 0.7 and 2%, it is noted that Engell discloses 1% radioimpurity in Example 2. Regarding the limitation wherein the purified flurpiridaz was prepared with a starting 18F activity of 200 GBq, up to about 500 GBq, See MPEP 2113. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). See also Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ("a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim").
Response to arguments
Applicant argues the pending claims, as amended, are directed to the discovery of a surprisingly purified flurpiridaz F18 compound, with very minimal amount of the specific identified and claimed radioimpurity compound, even when the radioactivity of the [18F]fluoride is significantly high - 1.e., greater than about 200 GBq - despite the fact that a higher starting radioactivity generally leads to greater radioimpurities due to increased radiodegradation, as the accompanying Grigg Declaration notes (Grigg Declaration 93,4). Applicant asserts that as also described in the Grigg Declaration, the instant specification and examples make clear that the teaching of the Engell reference does not include purified flurpiridaz as claimed, for example, when using the high starting radiation and/or optimized drying procedures (See Application at [0077], Grigg Declaration at ]5. Therefore, as confirmed by the Grigg Declaration, the cited Engell reference does not anticipate the specifically claimed amounts of the specific radioimpurity structure in a purified flurpiridiaz compound prepared with 200 GBq or higher radioactive [18F]fluoride at the start of preparation. Id. at 6.
Applicant’s arguments and the Declaration have been fully considered but are not found to be persuasive. It is respectfully submitted that Engell specifically recites that the amount of impurity is 1%, see Example 2. Regarding the arguments directed to the limitation wherein the purified flurpiridaz was prepared with a starting 18F activity of 200 GBq, up to about 500 GBq, See MPEP 2113. Product by process claims are not limited to the manipulations of the recited steps, only the structure implied by the steps. “[E]ven though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same as or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process.” In re Thorpe, 777 F.2d 695, 698, 227 USPQ 964, 966 (Fed. Cir. 1985) (citations omitted) (Claim was directed to a novolac color developer. The process of making the developer was allowed. The difference between the inventive process and the prior art was the addition of metal oxide and carboxylic acid as separate ingredients instead of adding the more expensive pre-reacted metal carboxylate. The product-by-process claim was rejected because the end product, in both the prior art and the allowed process, ends up containing metal carboxylate. The fact that the metal carboxylate is not directly added, but is instead produced in-situ does not change the end product.). Furthermore, "[b]ecause validity is determined based on the requirements of patentability, a patent is invalid if a product made by the process recited in a product-by-process claim is anticipated by or obvious from prior art products, even if those prior art products are made by different processes." Amgen Inc. v. F. Hoffmann-La Roche Ltd., 580 F.3d 1340, 1370 n 14, 92 USPQ2d 1289, 1312, n 14 (Fed. Cir. 2009). See also Purdue Pharma v. Epic Pharma, 811 F.3d 1345, 117 USPQ2d 1733 (Fed. Cir. 2016). However, in the context of an infringement analysis, a product-by-process claim is only infringed by a product made by the process recited in the claim. Id. at 1370 ("a product in the prior art made by a different process can anticipate a product-by-process claim, but an accused product made by a different process cannot infringe a product-by-process claim").
Conclusion
No claims are allowed at this time.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LEAH H SCHLIENTZ whose telephone number is (571)272-9928. The examiner can normally be reached Monday-Friday, 8:30am - 12:30pm EST.
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/LHS/
/Michael G. Hartley/ Supervisory Patent Examiner, Art Unit 1618