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
1. Claims 1-16 are pending in the current application.
2. This application is a 371 of PCT/EP2021/070801 07/26/2021; FOREIGN APPLICATIONS: EP 20187948.3 07/27/2020.
Objections
3. Claim 1 is objected to for the following informality: In step 5) “of formula” is repeated twice in the phrase “the free ligand of formula of formula 4”. Appropriate correction is required.
Claim interpretation
4. Claim 1 in steps 4) and 5) are drawn to “without isolating the compound1 from the solution of step 3)” and “without isolating the free ligand of formula 4 of formula 4”, respectively. The specification does not define the term isolating. The broadest reasonable interpretation of isolating is the process of separating a target compound from a complex mixture (like a reaction or natural product extract) using physical and chemical properties, often involving extraction, distillation, chromatography, or crystallization, to obtain a crude product. Common isolation techniques include but are not limited to:
liquid-liquid extraction where a separation occurs based upon on solubility between two immiscible solvents (water and organic solvent) often referred to as washing, or solvent washing. Variations include acid-base extractions, where acidic or basic compounds are converted to water-soluble salts and extracted into the aqueous layer;
chromatography (Column, TLC, HPLC): Separates based on differential partitioning between a solid stationary phase (silica, alumina, resins, etc.) and a mobile phase (solvent);
distillation: Separates liquids based on boiling points, involving heating and condensing vapors;
filtration: Separates solids from liquids using a porous filter;
crystallization.
Since each of these techniques is used in organic chemistry to separate individual compounds from a more complex matrix they constitute isolation in the broadest reasonable interpretation.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
5. Claims 7-11 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends. In claim 7 a number of isolation steps of compound formula 3 are listed including b. c. and .d which are solvent extraction/washing and other steps under “purifying” in steps c. as well as distillation in step d. (optional). Dependent claim 9 specifies that step c) is chromatography which is an isolation from the solution step. In a similar manner claim 10 describes an isolation of the compound of formula 4 which according to claim 4 is performed “without isolating the free ligand of formula of formula 4”. The acid/base extraction/washing, purifying and concentrating are all isolation steps. Purification is a form of separation/isolation from impurities. Claim 11 describes distillation, salt extraction, which is an isolation step. Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 103
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.
6. Claim(s) 1, 4-5, 13-14, 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Boi US 20180362511 A1 in view of Patrick, Graham Medicinal Chemistry, First Indian Reprint, 2015 Garland Science pages 188-195. The factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
Determination of the scope and content of the prior art (MPEP 2141.01)
Boi in Scheme 5 on pages 15-16 outlines the preparation of the compound of claim 1, compound 3, by the steps claimed:
PNG
media_image1.png
420
680
media_image1.png
Greyscale
PNG
media_image2.png
228
284
media_image2.png
Greyscale
PNG
media_image3.png
243
301
media_image3.png
Greyscale
Page 10 paragraph [0131] describes the process as follows:
PNG
media_image4.png
393
721
media_image4.png
Greyscale
On page 16, in the first step a), which is step 2):
Commercially available epichlorohydrin ( 4 . 1 mL ; 52 mmol ) was added to a solution of commercially available D-glucamine 1 ( 1 . 9 g ; 10 . 5 mmol ) in MeOH ( 110 mL ). The mixture was stirred at 50° C . for 26 h then evaporated to give the bridging molecule 2 as a colourless oil that was directly used for the next reaction without any further purification.
In the second step b), instant step 1) and 3) “protected ligand 3” is compound 3 of claim 1 and making a solution of 1A satisfies step 1A, the solvent being acetonitrile:
A solution of Substrate 1A (Org . Synth . 2008 , 85 , 10) (10 . 7 g ; 21 mmol ) in acetonitrile (14 mL) was added to a solution of compound 2 (3 . 8 g ; 10 . 5 mmol) in DMSO (14 mL) and Et N (4.3mL). The mixture was stirred at 70° C. for 72 h then evaporated. The residue was purified by chromatography on Amberlite XAD 1600 (eluent : gradient of water / MeCN) to give the protected ligand 3.
The 3rd step c) is instant step 4):
Trifluoroacetic acid ( 1 . 1 mL ) was added to a solution of 3 ( 2 . 1 g ; 1 . 6 mmol ) in dichloromethane ( 30 mL ) . The mixture stirred for 30 min then was evaporated. The residue was dissolved in TFA ( 3.7 mL ) and triisopropylsilane (0.1 mL) was added. The obtained mixture was stirred for 24 h at room temperature then evaporated and the residue purified by chromatography on Amberlite XE 750 column ( eluent : gradient of water/MeCN) obtaining the desired ligand 4 (1 .5 g).
Step d) is instant step 5):
[ 0230 ] Ligand 4 ( 1 . 5 g ; 1 . 5 mmol ) was dissolved in water ( 20 mL ) , gadolinium chloride hexahydrate ( 1 . 13 g ; 3 mmol ) was added then 1M NaOH was added to achieve pH 7 . The mixture was stirred at 50° C for 6 h . The solution was then filtered on Millipore HA 0 . 25 um filters and evaporated under reduced pressure. The crude product was purified on Amberchrome CG161M column ( eluent : gradient of water / acetonitrile ). The fractions containing the pure product were pooled and evaporated. The solid product was dried under vacuum to obtain the gadolinium complex.”
According to Patrick:
Minimizing the number of operations carried out during a process increases the overall yield. Isolation and purification of intermediates should be avoided, and it is best to keep intermediates in solution so that they can be easily transferred from one reaction vessel to another. Finding a solvent that is common to a series of reactions in the process is desirable. [Patrick page 193]
Once a suitable synthetic route has been identified, it is possible to increase the overall yield by reducing the number of operations that have to be carried out. One of the best ways of doing this is to develop the synthesis so that intermediates do not need to be isolated and purified.… On large scale, it is preferable to form one intermediate and keep it in solution for the next stage without attempting to isolate it. Therefore, using a solvent that is common to a series of reactions is preferable to using a different solvent for each reaction. [Page 194]
Patrick explains that “Concentrating solutions to dryness should be avoided since dry solids cannot be removed from the reaction vessel. It is better to keep intermediates in solution, so that they can be easily transferred from one reaction vessel to another.” [Page 192]. Patrick also explains that “Reagents used in the initial synthesis of a drug are often unsuitable for a large-scale synthesis due to their cost or the hazards associated with their use...The starting materials for a synthesis should be cheap and readily available. The hazards of starting materials and intermediates should be considered.” [page 188] “Some reagents are unsuitable for large-scale synthesis on safety grounds.” [Page 189]
Ascertainment of the difference between the prior art and the claims
The prior art differs only in a “without isolation” limitation in the instant claims and the use of “aqueous solvent”.
Finding of prima facie obviousness
Rationale and Motivation
(MPEP 2142-2143)
The claimed procedure use water or “aqueous solvent” as solvent and “without isolation”, although the meaning of “without isolation” is ambiguous. Since the prior art uses certain organic solvents like halogenated hydrocarbons avoiding these on scale is advisable.
Reducing the use of organic solvents, and in particular halogenated hydrocarbons is advisable, as they are harmful both environmentally and physiologically and can contaminate the drug substance. As Patrick explains, “Isolation and purification of intermediates should be avoided, and it is best to keep intermediates in solution so that they can be easily transferred from one reaction vessel to another”, which would motivate the artisan to alter the process “without isolation”.
It would have also been prima facie obvious to one of ordinary skill in the art at the time the invention was made to use water or “aqueous solvent” as solvent and “without isolation”. Since water is used in the penultimate step and “finding a solvent that is common to a series of reactions in the process is desirable”, using an aqueous solvent would be preferred on scale-up. Using water in the deprotection step would allow the use of aqueous acids like HCl and sulfuric acid which are cheap and better alternatives on a large scale to the use of TFA as was done in the prior art.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole was prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
7. Claim(s) 7-12 is/are rejected under 35 U.S.C. 103 as being unpatentable over Boi in view of Patrick as applied to claim 1, 4-5, 13-14 above, and further in view of Jasperse, Craig "Liquid liquid extractions" Minnesota State University, page 63-68, Online: “https://web.mnstate.edu/jasperse/Chem355/Acid-Base%20Extraction.doc.pdf” dated by the wayback machine to May 16, 2018. Jasper explains on page 63:
The most common and simple separation in organic chemistry involves the separation of neutral organics from ionic compounds, whether the ionic compound is an inorganic salt (NaCl) or is an ionized version of the organic. The two most commonly ionized organic families are carboxylic acids, which are ionized by deprotonation to their carboxylate RCO2- form, or basic amines, which are ionized by protonation to their ammonium RNH3+ form. Neutrals and ionics are easily separated because ionics are preferably soluble in water rather than in organic solvents, whereas neutral organics are preferably soluble in organic solvents rather than in water….
2. Isolating a neutral carboxylic acid from the NaOH/water layer:
• Acidify/Neutralize HCl is added to acidify the water. In the process the carboxylate anion RCO2- is protonated and reverts to its neutral form RCO2H.
• Filter or Extract Because the acid is now neutral, its solubility in water will be low.
If it crystallizes, you can filter it. If it comes out of the water as an oil, you can extract it in ether!
3. Isolating a neutral amine from the HCl/water layer:
• Basify/NeutralizeNaOH is added to basify the water. In the process the ammonium
cation RNH3+ is deprotonated and converted back to its neutral form RNH2.
• Filter or Extract Because the amine is now neutral, its solubility in water will
be low. If it crystallizes, you can filter it. If it comes out of the water as an oil, you
can extract it in ethe
Claims 10-12 are drawn to using an acid base extraction in steps ii) and iii). Carboxylic acids are typically separated this way. Since the prior art is on a small scale and uses direct evaporation and chromatography to purify the compounds, it would be obvious to conduct the “most common and simple” purification on the carboxylates on a large scale, acid/base extraction. Claims 7-9 uses an acid base extraction to isolate the amine 3, amines are typically separated this way. Since the prior art is on a small scale and uses direct evaporation and chromatography to purify the compounds, it would be obvious to conduct the “most common and simple” purification on the amines on a large scale, acid/base extraction.
8. Claim(s) 2-3, 6 is/are rejected under 35 U.S.C. 103 as being unpatentable over Boi in view of Patrick as applied to claim 1, 4-5, 13-14 above, and further in view of Moore WO 2007/064661. Claims 2-3 are drawn to using compound 1A as the HBr salt, while the Boi process uses the free base. Amine salts are more stable solids and easier to manipulate and are generally preferred on scale. The HBr salt is commercial and well-known and used for the same type of synthetic elaboration in Moore on page 25:
[00156] Synthesis of 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, 10-[2-t-butoxv-5-nitrophenyl)methyl]-, tri-t-butyl ester, sodium bromide complex (3)
[00157] 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, tri-t-butyl ester hydrobromide, 8.46g 0.0142 mole, was stirred with aqueous sodium hydroxide, 0.1N 200mL, and diethyl ether, 200mL. When the entire solid had dissolved, the organic phase was collected and the aqueous phase washed with diethyl ether, 2x200mL…..
Since the HBr salt of compound 1A was known and used in the same way in the art it cannot be considered inventive to substitute this compound in the process of the prior art.
Claim 6 is drawn to the process of the prior art with DMAC as solvent for the substitution reaction of epichlorohydrin and glucamine. In the prior art process of Boi the reaction was performed in methanol, however a polar aprotic solvent like DMAC would work well for the ring opening of the epoxide. In the reaction to make compound 1A, Moore uses DMAC as solvent as shown on page 24:
[00154] Synthesis of 1,4,7,10-Tetraazacyclododecane-1,4,7-triacetic acid, tri-t-butyl ester Hydrobromide (2)
[00155] Cyclen, 32.0g 0.186mole, and sodium acetate trihydrate, 75.8 g 0.557mole, were stirred with dimethylacetamide, 600mL, for one hour. To this mixture was added a solution of /-butyl bromoacetate, 109g 0.557mole, in dimethylacetamide…
By using the same solvent that had been used to prepare the other coupling partner, (1A), in the reaction to form (2), the number of solvents would be reduced. This is in keeping with the principle outlined by Patrick discussed above, “[U]sing a solvent that is common to a series of reactions is preferable to using a different solvent for each reaction.”
9. Claim(s) 16 is/are rejected under 35 U.S.C. 103 as being unpatentable over Boi in view of Patrick as applied to claim 1, 4-5, 13-14 above, and further in view of Moore WO 2007/064661 and further in view of Walker, Derek “The Management of Chemical Process Development in the Pharmaceutical Industry” 2008 John Wiley & Sons, page 186. As discussed above the prior art aqueous solution containing the product was dried by evaporation however no description of spray drying was given. Walker explains “Spray dryers are also normally employed for the removal of water…. Of the above three drying techniques, spray drying is probably the most widely used, especially in recovering water-soluble drug substances from water solution (e.g.,the aminoglycosides).” It would be obvious to spray dry the compound from the prior art water solution.
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 claims at issue 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); and 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 a nonstatutory double patenting ground provided the reference application or patent either is shown to be commonly owned with this application, or claims an invention made as a result of activities undertaken within the scope of a joint research agreement. A terminal disclaimer must be signed in compliance with 37 CFR 1.321(b).
The USPTO internet Web site contains terminal disclaimer forms which may be used. Please visit http://www.uspto.gov/forms/. The filing date of the application will determine what form 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 http://www.uspto.gov/patents/process/file/efs/guidance/eTD-info-I.jsp.
10. Claims 1-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-21 of U.S. Patent No. 12,384,802. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims of the ‘802 patent while drawn to the use of the organic solvent (MTBE) in the step a) by deprotonating the HBr salt with base, the instant claims are drawn to any method of preparing the compound 1A. The rest of the steps are the same. According to claim 2-3 the preparing step of claim 1 is the reaction of the HBr salt with base. Since the applicant has already received a patent for the narrower process with MTBE, a separate patent cannot be granted on the genus encompassing MTBE solvent, since it anticipates the claims. Besides that consideration, MTBE is a good solvent, non-explosive, embraced by the instant claims and would be a good choice.
11. Claims 1-16 rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-42 of U.S. Patent No. 12,290,576 in view of Tear “Towards an Improved Design of MRI Contrast Agents: Synthesis and Relaxometric Characterisation of Gd-HPDO3A Analogues” Chem. Eur. J. 2020, 26, 6056 – 6063, First Published online: 05 March 2020. Although the claims at issue are not identical, they are not patentably distinct from each other because the patent claims of the ‘576 patent are drawn to a particular amount of the Gd salt 1.025 equivalents,2 while the instant claims are drawn to any amount. Since the applicant has already received a patent for the narrower process with a specific amount, separate patent cannot be granted on the genus encompassing the specific amount since it anticipates the claims. Besides this consideration, since free Gd3+ ions in have a known toxic effect in humans, their presence in a Gd(III) complex which are used in human imaging is tightly controlled. In a similar manner, a free chelating ligand uncomplexed to Gd is also toxic since such ligands remove metal centers from enzymes and various other biomolecules which form part of the cellular machinery. Free Gd3+ or ligand may be present due to an incomplete complexation step during synthesis and for this reason the complexation reactions are closely monitored to assure completeness. Aresenazo (III) dye test or a similar spectrophotometric test with xylenol orange may be used to detect the presence of free lanthanide ions. This process is illustrated by Tear in the preparation of a similar Gd complex HEDO3A, shown in figure 1 on page 6057. The preparation of the compound is given on col. 2 of page 6062:
Gd-HEDO3A: The1,4,7,10-tetraazacyclododecane-10-(2-hydroxyethyl)- 1,4,7-triacetic acid tetrahydrochloride (4) (150 mg;0.3 mmol) was dissolved in water (10 mL) and basified to pH7 with NaOH 0.1N. A solution of GdCl3 in water was gradually added, while maintaining pH7 with NaOH 0.1N, until the presence of residual free Gd3+ in the solution was confirmed by the orange xylenol UV method.[35] The product was purified by chromatography on an Amberchrom CG161 resin (eluent: water/ACN gradient). The fraction containing the pure product was evaporated and freeze dried.
The exact amount is not given but was capable of being determined by the artisan of ordinary skill. Optimization of this process is within the scope of what one skilled in the art would be capable. All of this is especially true in light of the clear teaching that these parameters are results effective and have to be optimized. The ordinary artisan is well aware that “discovery of an optimum value of a result effective variable . . . is ordinarily within the skill of the art.” In re Boesch, 617 F.2d 272, 276 (CCPA 1980).
12. Claims 1-16 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 24-25 of copending Application No. 18/718,945. Although the claims at issue are not identical, they are not patentably distinct from each other because the process of the ‘945 patent includes all of the steps of the instant claims vis a vis the independent claim 1.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Conclusion
13. Any inquiry concerning this communication or earlier communications from the examiner should be directed to DAVID K O'DELL whose telephone number is (571)272-9071. The examiner can normally be reached on Monday - Friday 9:30 - 7:00 PM.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Clinton Brooks can be reached on 571-270-7682. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of an application may be obtained from Patent Center. Status information for published applications may be obtained from Patent Center. Status information for unpublished applications is available through Patent Center for authorized users only. Should you have questions about access to Patent Center, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free).
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) Form at https://www.uspto.gov/patents/uspto-automated- interview-request-air-form.
/DAVID K O'DELL/Primary Examiner, Art Unit 1621 she
1 “the compound” is ambiguous but presumably this is the compound 3 since it is obtained as a solution in step 3).
2 The reaction stoichiometry is such that 1 mol of ligand of formula requires 2 mol of Gd and the patent claims are drawn to 2.05 molar ratio.