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 .
Election/Restrictions
Applicants’ election without traverse of Group I (i.e., claims 1-37, drawn to a process of solid phase peptide synthesis); in the reply filed on 05/05/2026 is acknowledged.
Claims 38-45 are withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a nonelected invention, there being no allowable generic or linking claim. Election was made without traverse in the reply filed on 05/05/2026.
Priority
This application claims the benefit of pending U.S. Patent Application No. 63/401,349, filed August 26, 2022; pending U.S. Patent Application No. 63/442,216, filed January 31, 2023; pending U.S. Patent Application No. 63/452,550, filed March 16, 2023; pending U.S. Patent Application No. 63/452,674, filed March 16, 2023; pending U.S. Patent Application No. 63/521,623, filed June 16, 2023; and pending U.S. Patent Application No. 63/532,041, filed August 10, 2023.
Status of Claims
Claims 1-45 were originally filed on 08/24/2023. Claims 38-45 are withdrawn.
Claims 1-37 are currently pending and under consideration.
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 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.
Claims 1-14, 19-31, and 34-37 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0194246 (published 06/27/2019, cited in IDS filed on 07/11/2024) in view of US 2003/0000473 (published 01/02/2003, cited in IDS filed on 07/11/2024).
US’246 teaches an improved method of deprotection in solid phase peptide synthesis is disclosed. In particular the deprotecting composition is added in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle. Thereafter, the ambient pressure in the vessel is reduced with a vacuum pull to remove the deprotecting composition without any draining step and without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle (see Abstract).
Regarding claim 1, US’246 teaches a method of deprotection in solid phase peptide synthesis [0016]. In another aspect the invention is a method of deprotection in solid phase peptide synthesis (SPPS) in which the improvement comprises deprotecting a protected amino acid at a temperature of at least about 60° C (see [0018]). US’246 specifies that raising the temperature to 60° C greatly encourages the desired evaporation (see [0044]). In exemplary methods, the pressure can be reduced to below atmospheric pressure, or, expressed in terms of temperatures, the deprotection step can be carried out by heating the compositions to at least about 60° C., and in some cases to between about 81° C. and 99° C., after which the vessel contents can be heated to between about 90° and 110° to accelerate the vacuum removal step (see [0046]).
US’246 discloses the use of nitrogen, which is helpful under these circumstances because it is relatively inexpensive, widely available, and inert to the reactions being carried out and to the equipment in the instrument or system. It will thus be understood that other inert gases, including the noble gases, can be used for this purpose (see [0055]).
US’246 further illustrates a nitrogen supply 54 which is connected to a plurality of supply bottles 55 which for schematic purposes are illustrated as Erlenmeyer flasks. A plurality of metered loops are schematically illustrated by lines 56, 57, and 58 and connect the nitrogen supply to the supply bottles 55; and corresponding lines 60, 61, and 62 then connect to a common line 63 that reaches the spray head 53 for delivery to the vessel 22 (see FIG. 7, [0054]). US’246 specifies a separate line 63 provides nitrogen from the source 54 to the liquids and resin in the vessel 22 to agitate (bubble) the contents of the vessel 22 to carry out appropriate mixing and circulation during deprotection, coupling, and cleavage reactions (see [0054]), providing a path for evaporating base to leave the reaction vessel (see [0018]).
US’246 does not disclose a portion of the deprotecting base evaporates into an upper interior portion of the reaction vessel during the removing of the protecting group of the protected amino acid; and directing an inert gas through the reaction vessel to remove evaporated deprotecting base from the interior of the reaction vessel during the removing the protecting group of the protected amino acid.
US’473 teaches the shower head appropriate for carrying out the above method is installed at the upper portion of a reaction chamber in which a substrate is seated on the lower portion. The shower head has a gas supply line formed on the upper surface of the shower head for receiving a first reaction gas from a supply source of the first reaction gas; gas supply lines formed on the upper surface of the shower head for receiving other reaction gases from a supply source of the other reaction gases; a plurality of outlets for the first reaction gas formed along the edge of the lower surface of the shower head for discharging the first reaction gas; a plurality of outlets for each of the other reaction gases formed on the central portion of the lower surface of the shower head, for discharging the other reaction gases; a gas passage formed within the body of the shower head, for connecting the gas supply line for the first reaction gas to the plurality of outlets for the first reaction gas; and gas passages formed independently of the gas passage for the first reaction gas within the body of the shower head, for connecting the supply lines for the other reaction gases to the plurality of outlets for each of the other reaction gases (see [0012]).
US’473 illustrates a cross-sectional view illustrating the configuration of another embodiment of a shower head used in a gas delivery method according to the present invention (see FIG. 8, [0023]). US’473 shows the interior of the shower head 60 has passages for first and second reaction gases to prevent the first and second reaction gases from being mixed. In particular, one reaction gas is allowed to be discharged to outlets 72 formed around the outer edge of the bottom surface of the shower head 60, and the other reaction gas is allowed to be discharged to outlets 74 formed in a central portion of the bottom surface of the shower head 60 (see Fig 7, [0028]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify process of US’246 by using a spray head a taught by US’473. The motivation being to provide a spray head for the introduction of a gas within a reaction vessel that ensures the entirety of the reaction vessel is contacted with the flow of inert gas.
Regarding claim 2, US’246 discloses adding the deprotecting composition in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle (see [0016]). In another aspect the invention is a method of deprotection in solid phase peptide synthesis in which the improvement comprises adding the deprotecting composition in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle (see [0020]).
Regarding claims 3-5, US’246 teaches the step of adding the deprotecting base is usually carried out by adding a sufficient volume of relatively low concentration that will cover the drained resin in the reaction vessel and the attached peptide after the coupling step to ensure that both the scavenging and deprotection reactions take place (see [0013]). As a further advantage, the high concentration allows the organic base to be added in a proportionally small volume with a ratio of between about 1:20 and 1:3 being appropriate based upon the volume of the coupling solution. Piperidine or pyrrolidone or 4-methylpiperidine can be added in the volume ratio of about 1:5 based upon the volume of the coupling solution when added neat. In such circumstances, the small volume of the deprotecting solution is typically less than 2 ml, and often less than one milliliter. In exemplary circumstances, between about 0.4 and 1.0 ml of piperidine are added to between about 3.8 and 4.2 ml of the mixture of the coupling solution, the growing peptide chain and any excess activated acid (see [0038]). Expressing the proportion as a percentage, the small volume of the deprotecting solution is 20% or less of the volume of the mixture of the coupling solution, the growing peptide chain (see [0039]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a deprotecting agent in an amount from about 1 vol% to about 5 vol% based on the total volume of the deprotecting composition, to achieve optimum or workable ranges. The motivation for doing so would have been to use an optimized concentration deprotecting agent that enables deprotection of a protected amino acid within a composition that enables evaporation of excess deprotecting agent.
Regarding claim 6, US’246 schematically illustrates a few additional details of the system for carrying out the method of the invention. In FIG. 7 the vessel is again designated at 22, and FIG. 7 further illustrates that the vessel 22 includes a frit 52 (typically made of glass) and a spray head 53. The frit 52 permits liquids to be drained from the reaction vessel 22 and the spray head 53 delivers compositions to the reaction vessel 22. Other equivalent fixtures can be selected by the skilled person without undue experimentation (see FIG. 7, [0053]).
US’246 does not disclose wherein the spray head comprises at least one inner side wall positioned in the outer interior space and extending around an inner interior space, and a plurality of holes extending at least partially around the inner interior space, the inner and outer interior spaces are in fluid communication with one another by way of holes of the plurality of holes, and the directing step comprises directing the first inert gas through the first opening into the inner interior space and out holes of the plurality of holes into the outer interior space.
US’473 teaches the shower head appropriate for carrying out the above method is installed at the upper portion of a reaction chamber in which a substrate is seated on the lower portion. The shower head has a gas supply line formed on the upper surface of the shower head for receiving a first reaction gas from a supply source of the first reaction gas; gas supply lines formed on the upper surface of the shower head for receiving other reaction gases from a supply source of the other reaction gases; a plurality of outlets for the first reaction gas formed along the edge of the lower surface of the shower head for discharging the first reaction gas; a plurality of outlets for each of the other reaction gases formed on the central portion of the lower surface of the shower head, for discharging the other reaction gases; a gas passage formed within the body of the shower head, for connecting the gas supply line for the first reaction gas to the plurality of outlets for the first reaction gas; and gas passages formed independently of the gas passage for the first reaction gas within the body of the shower head, for connecting the supply lines for the other reaction gases to the plurality of outlets for each of the other reaction gases (see [0012]). US’473 discloses a cross-sectional view illustrating the configuration of another embodiment of a shower head used in a gas delivery method according to the present invention (see FIG. 8, [0023]). Additionally, US’473 discloses the interior of the shower head 60 has passages for first and second reaction gases to prevent the first and second reaction gases from being mixed. In particular, one reaction gas is allowed to be discharged to outlets 72 formed around the outer edge of the bottom surface of the shower head 60, and the other reaction gas is allowed to be discharged to outlets 74 formed in a central portion of the bottom surface of the shower head 60 (see FIG 7, [0028]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to modify process of US’246 by using a spray head a taught by US’473. The motivation being to provide a spray head for the introduction of a gas within a reaction vessel that ensures the entirety of the reaction vessel is contacted with the gas.
Regarding claim 7, US’473 teaches a shower head installed at an upper portion of a reaction chamber in which a substrate is seated on a lower portion thereof, so as to supply two or more mutually-reactive reaction gases, the shower head comprising: a gas supply line formed on an upper surface of the shower head for receiving a first reaction gas from a supply source of the first reaction gas; gas supply lines formed on the upper surface of the shower head for receiving other reaction gases from respective supply sources of the other reaction gases; a plurality of outlets for the first reaction gas formed along an outer edge of a lower surface of the shower head for discharging the first reaction gas; a plurality of outlets for each of the other reaction gases formed on a central portion of the lower surface of the shower head for discharging the other reaction gases (see claim17).
Regarding claim 8, US’473 discloses the first reaction gas is delivered downward via gas outlets formed around an upper edge of the reaction chamber, and the other reaction gases are delivered downward via gas outlets formed on a central portion of an upper side of the reaction chamber (see claim 10). US’473 further discloses the gas delivery method, wherein the first reaction gas is delivered laterally via gas outlets formed on a side surface of the reaction chamber, and the other reaction gases are delivered downward via gas outlets formed on a central portion of an upper side of the reaction chamber (see claim 11). US’473 teaches the gas delivery method, wherein the first reaction gas is delivered upward via gas outlets formed along an edge of a bottom surface of the reaction chamber, and the other reaction gases are delivered downward via gas outlets formed on a central portion of an upper side of the reaction chamber (see claim 12). A shower head installed at an upper portion of a reaction chamber in which a substrate is seated on a lower portion thereof, so as to supply two or more mutually-reactive reaction gases, the shower head comprising: a gas supply line formed on an upper surface of the shower head for receiving a first reaction gas from a supply source of the first reaction gas; gas supply lines formed on the upper surface of the shower head for receiving other reaction gases from respective supply sources of the other reaction gases; a plurality of outlets for the first reaction gas formed along an outer edge of a lower surface of the shower head for discharging the first reaction gas; a plurality of outlets for each of the other reaction gases formed on a central portion of the lower surface of the shower head for discharging the other reaction gases; a gas passage formed within a body of the shower head for connecting the gas supply line for the first reaction gas to the plurality of outlets for the first reaction gas; and gas passages formed independently of the gas passage for the first reaction gas within the body of the shower head for connecting the supply lines for the other reaction gases to the plurality of outlets for each of the other reaction gases (see claim 17). Additionally, US’473 teaches the shower head, wherein the plurality of outlets for the first reaction gas are extended further downward toward the substrate than the plurality of outlets for each of the other reaction gases, such that the plurality of outlets for the first reaction gas are closer to the substrate than the plurality of outlets for each of the other reaction gases when the shower head is installed in the upper portion of the reaction chamber (see claim 18).
Regarding claim 9, US’246 teaches that the system uses nitrogen pressure for transfer of all reagents and to provide an inert environment during synthesis. Nitrogen bubbling is used for mixing during deprotection, coupling, and cleavage reactions (see [0063]).
Regarding claim 10, US’246 also teaches the pressure can be reduced to below atmospheric pressure, or, expressed in terms of temperatures, the deprotection step can be carried out by heating the compositions to at least about 60° C., and in some cases to between about 81° C. and 99° C., after which the vessel contents can be heated to between about 90° and 110° to accelerate the vacuum removal step. Functionally, the vacuum and the applied microwave power should provide the intended enhanced evaporation without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle (see [0046]).
Regarding claim 11, US’246 teaches as the boiling point of piperidine is approximately 106° C. and that of DMF is about 153° C., the vapor pressure of piperidine will be higher than the vapor pressure of DMF at any given temperature. Accordingly it has now been discovered that pulling a moderate vacuum from the vessel can selectively remove the piperidine and completely avoid the draining step. FIG. 5 illustrates this schematically by showing the deprotection step 23 followed by an evaporation step 36 followed by the draining step (of liquids other than the organic base) and then the coupling step 27. The boiling point of 4-methylpiperidine is 123° C., offering similar advantages (see [0043]).
Regarding claim 12, US’246 discloses in the exemplary embodiment, pyrrolidine can be added (see FIG. 1[0030], [0037]).
Regarding claim 13, US’246 teaches the high concentration allows the organic base to be added in a proportionally small volume with a ratio of between about 1:20 and 1:3 being appropriate based upon the volume of the coupling solution. Piperidine or pyrrolidone or 4-methylpiperidine can be added in the volume ratio of about 1:5 based upon the volume of the coupling solution when added neat. In such circumstances, the small volume of the deprotecting solution is typically less than 2 ml, and often less than one milliliter. In exemplary circumstances, between about 0.4 and 1.0 ml of piperidine are added to between about 3.8 and 4.2 ml of the mixture of the coupling solution, the growing peptide chain and any excess activated acid (see [0038]). Expressing the proportion as a percentage, the small volume of the deprotecting solution is 20% or less of the volume of the mixture of the coupling solution, the growing peptide chain, and any excess activated acid (see [0039]).
Regarding claim 14, the teachings of US’246 are stated above. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the process of US’246 by adding deprotection solution including the deprotecting base to the reaction vessel in an amount sufficient than zero to about 30 vol%.
Regarding claim 19, the teachings are stated above. Same as instant claim 1 except there is mention of coupling of second amino acid to the deprotected amino acid to form a peptide from the first, which is taught by US’246. US’246 teaches an amino acid is attached to a solid phase particle by a linking group on the acid side, and to a protecting group on the amine side. The protecting group is removed so that the second acid (and in particular it's acid group) can be coupled to the amine group on the original acid (see [0006]).
Regarding claim 20, same as taught above. Additionally, as US’246 teaches the second (and succeeding) acids are also initially protected, and thus the general sequence is to deprotect, couple, and repeat until the desired peptide is completed, following which the completed peptide is cleaved from the solid phase resin (see [0006]).
Regarding claim 21, as taught above. In another aspect, US’246 teaches is a method of deprotection in solid phase peptide synthesis in which the improvement comprises adding the deprotecting composition in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated acid from the preceding coupling cycle, and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle (see [0020]).
Regarding claims 22-23, US’246 teaches the step of adding the deprotecting base is usually carried out by adding a sufficient volume of relatively low concentration that will cover the drained resin in the reaction vessel and the attached peptide after the coupling step to ensure that both the scavenging and deprotection reactions take place (see [0013]). As a further advantage, the high concentration allows the organic base to be added in a proportionally small volume with a ratio of between about 1:20 and 1:3 being appropriate based upon the volume of the coupling solution. Piperidine or pyrrolidone or 4-methylpiperidine can be added in the volume ratio of about 1:5 based upon the volume of the coupling solution when added neat. In such circumstances, the small volume of the deprotecting solution is typically less than 2 ml, and often less than one milliliter. In exemplary circumstances, between about 0.4 and 1.0 ml of piperidine are added to between about 3.8 and 4.2 ml of the mixture of the coupling solution, the growing peptide chain and any excess activated acid (see [0038]). Expressing the proportion as a percentage, the small volume of the deprotecting solution is 20% or less of the volume of the mixture of the coupling solution, the growing peptide chain (see [0039]).
It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to use a deprotecting agent in an amount from about 1 vol% to about 5 vol% based on the total volume of the deprotecting composition, to achieve optimum or workable ranges. The motivation for doing so would have been to use an optimized concentration deprotecting agent that enables deprotection of a protected amino acid within a composition that enables evaporation of excess deprotecting agent.
Regarding claims 24-26, see the teachings same as for claims 6-8. Additionally, US’473 teaches the shower head appropriate for carrying out the above method is installed at the upper portion of a reaction chamber in which a substrate is seated on the lower portion. The shower head has a gas supply line formed on the upper surface of the shower head for receiving a first reaction gas from a supply source of the first reaction gas; gas supply lines formed on the upper surface of the shower head for receiving other reaction gases from a supply source of the other reaction gases; a plurality of outlets for the first reaction gas formed along the edge of the lower surface of the shower head for discharging the first reaction gas; a plurality of outlets for each of the other reaction gases formed on the central portion of the lower surface of the shower head, for discharging the other reaction gases; a gas passage formed within the body of the shower head, for connecting the gas supply line for the first reaction gas to the plurality of outlets for the first reaction gas; and gas passages formed independently of the gas passage for the first reaction gas within the body of the shower head, for connecting the supply lines for the other reaction gases to the plurality of outlets for each of the other reaction gases (see [0012]).
Regarding claims 27 and 28, US’246 teaches that the system uses nitrogen pressure for transfer of all reagents and to provide an inert environment during synthesis. Nitrogen bubbling is used for mixing during deprotection, coupling, and cleavage reactions (see [0063]). US’246 also teaches the pressure can be reduced to below atmospheric pressure, or, expressed in terms of temperatures, the deprotection step can be carried out by heating the compositions to at least about 60° C., and in some cases to between about 81° C. and 99° C., after which the vessel contents can be heated to between about 90° and 110° to accelerate the vacuum removal step. Functionally, the vacuum and the applied microwave power should provide the intended enhanced evaporation without otherwise adversely affecting the remaining materials in the vessel or causing problems in subsequent steps in the SPPS cycle (see [0046]).
Regarding claim 29, US’246 teaches pyrrolidine can be added (see FIG. 1[0030], [0037]).
Regarding claim 30, US’246 teaches the high concentration allows the organic base to be added in a proportionally small volume with a ratio of between about 1:20 and 1:3 being appropriate based upon the volume of the coupling solution. Piperidine or pyrrolidone or 4-methylpiperidine can be added in the volume ratio of about 1:5 based upon the volume of the coupling solution when added neat. In such circumstances, the small volume of the deprotecting solution is typically less than 2 ml, and often less than one milliliter. In exemplary circumstances, between about 0.4 and 1.0 ml of piperidine are added to between about 3.8 and 4.2 ml of the mixture of the coupling solution, the growing peptide chain and any excess activated acid (see [0038]). Expressing the proportion as a percentage, the small volume of the deprotecting solution is 20% or less of the volume of the mixture of the coupling solution, the growing peptide chain, and any excess activated acid (see [0039]).
Regarding claim 31, the teachings of US’246 are stated above. It would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention to optimize the process of US’246 by adding deprotection solution including the deprotecting base to the reaction vessel in an amount sufficient than zero to about 30 vol%.
Regarding claim 34, US’246 teaches combining both improvements as illustrated by the differences between FIG. 1 and FIG. 5 and can allow the cycle to avoid both the washing steps and two of the draining steps (see [0048]).
Regarding claims 35 and 36, US’246 teaches the SPPS deprotection step is typically carried out by adding an organic base to the protected acid, then draining the reaction vessel—one of the advantages of SPPS is that the organic compounds can be handled as if they were solids—then washing the deprotected chain (see [0010]).
It is obvious to use “2 times or less of the bed volume of resin present in the reaction vessel”. US’246 further teaches, in most circumstances, a wash repeated five times is both typical and satisfactory to remove anything that might create different sequences or undesired byproducts. The coupling step is then carried out followed by another draining step, and another repetitive wash, with five washes again being typical (see [0010]).
Regarding claim 37, the teachings are stated above. Same as instant claims 1 and 19, in addition to teachings by US’246, the step of adding the deprotecting base is usually carried out by adding a sufficient volume of relatively low concentration that will cover the drained resin in the reaction vessel and the attached peptide after the coupling step to ensure that both the scavenging and deprotection reactions take place (see [0013]).
Claims 15-18, 32, and 33 are rejected under 35 U.S.C. 103 as being unpatentable over US 2019/0194246 (published 06/27/2019, cited in IDS filed on 07/11/2024) as applied to claims 1-14; 19-31 and 34-36, above, and further in view of Merrifield (Solid Phase Peptide Synthesis. I. The Synthesis of a Tetrapeptide; R. B. Merrifield, Journal of the American Chemical Society, Vol 85/Issue 14, published July 1, 1963, cited in IDS filed on 07/11/2024).
Regarding claims 15 and 16, US’246 discloses use of Spheritide™ resin (0.66 meq/g substitution) (see [0065]); reaction vessel for 0.025-1.0 millimole (mmol) syntheses (see [0063]); and the peptides were synthesized at 0.05mmol scale with 10 equivalents of amino acid (see [0074]).
However, US’246 is silent about protected amino acid being attached to solid resin.
Merrifield teaches polystyrene resin was used, the quantity of amino acid attached to the resin was purposely limited to approximately 0.5mmole per gram of substituted polymer (see Attachment of the First Amino Acid to the Polymer, 1st paragraph, page 2150).
Regarding claim 17, US’246 teaches all Fmoc amino acids were obtained from Novabiochem (San Diego, CA) and contained the following side chain protecting groups [0068] Coupling reactions were performed in the presence of a 5-fold molar excess of 0.2 M Fmoc-protected amino acids (see [0060]). US’246 specifies the reaction vessel for 0.025-1.0 millimole (mmol) syntheses [0063], the peptides were synthesized at 0.05mmol scale with 10 equivalents of amino acid (see [0074]). Additionally, US’246 discloses a method of deprotection in solid phase peptide synthesis (SPPS) in which the improvement comprises deprotecting a protected amino acid at a temperature of at least about 60° C (see [0018]) and the deprotection step was performed … at 95° C. and initiated by adding … pyrrolidine directly to the coupling solution (see [0074]).
US’246 does not specifically disclose regarding the mode of linkage between the peptide and resin.
Merrifield teaches to provide a point of attachment for the peptide, the polystyrene resin was partially chloromethylated, the product was then nitrated or brominated. The resulting substituted chloromethyl polystyrene was treated with the tri ethyl ammonium salt of the first protected amino acid in the proposed peptide chain to give a substituted benzyl ester linkage (Attachment of the First Amino Acid to the Polymer, 1st paragraph, page 2150).
Regarding claim 18, the teachings of US’246 and Merrifield are stated above. Additionally, US’246 discloses a method of deprotection in solid phase peptide synthesis which includes the steps of adding the deprotection composition in high concentration and small volume to the mixture of the coupling solution, the growing peptide chain, and any excess activated amino acid from the preceding coupling cycle; and without any draining step between the coupling step of the previous cycle and the addition of the deprotection composition for the successive cycle which removes at least 50% of the volume of the previous cycle coupling solution (see [0021]). US’246 further teaches the deprotection solution is then drained (step 24) following which a washing liquid (e.g., methanol or isopropanol) is added to the vessel for a washing step 25 carried out repetitively with five repetitions being typical. The washing solution is then removed in a second draining step 26 which allows the coupling step 27 to take place. The coupling composition is then removed in a third draining step 30 followed by a second washing step 31, again repeated five times (see [0031]).
Regarding claim 32 and 33, same as taught above. US’246 discloses use of Spheritide™ resin (0.66 meq/g substitution) (see [0065]); reaction vessel for 0.025-1.0 millimole (mmol) syntheses (see [0063]); and the peptides were synthesized at 0.05mmol scale with 10 equivalents of amino acid (see [0074]). However, US’246 is silent about protected amino acid being attached to solid resin. Merrifield teaches polystyrene resin was used, the quantity of amino acid attached to the resin was purposely limited to approximately 0.5mmole per gram of substituted polymer (see Attachment of the First Amino Acid to the Polymer, 1st paragraph, page 2150).
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.
Claims 1-37 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1, 2, 9, 12, 13, 15, 21, 24, 35, 37-43, 48, 52, 54, 57, 60-65, 70, 74, 76, 79, 80-82, and 104 of copending Application No. 18/689,968 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other because the reference claims anticipate the instant claims.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Reference claim 1 recites a process for deprotecting a protected amino acid during solid phase peptide synthesis, comprising: heating a protected amino acid and a deprotecting agent in a lower interior portion of a reaction vessel during a deprotection reaction removing a protecting group from the protected amino acid, wherein the heating step volatizes deprotecting agent into an upper interior portion of the reaction vessel; and directing a first inert gas into the upper interior portion of the reaction vessel through a first opening in an upper portion of the reaction vessel and out of the upper interior portion of the reaction vessel through a second opening in the upper portion of the reaction vessel during the heating step to remove volatized deprotecting agent from the interior of the reaction vessel during the deprotection reaction. Reference claim 2 recites the process comprising continuously directing the first inert gas through the upper interior portion of the reaction vessel during the heating step to remove volatized deprotecting agent from the interior of the reaction vessel during the deprotection reaction. Regarding heating temperature conditions, the reference specification states the heating step of any of the embodiments of the deprotection processes disclosed herein may be conducted, for example, at a temperature from about 40°C to about 120°C, as another example about 50°C to about 120°C, and as another example about 70°C to about 120°C (see [0025]). Regarding the vol% deprotecting composition, the instant specification discloses the deprotecting composition includes a deprotecting agent in an amount of about 5 vol% or less, based on the total volume of the deprotecting composition. For example, the deprotecting composition may include the deprotecting agent in an amount from about 2 vol% to about 5 vol%, for example from about 2 to about 4.5 vol%, for example from about 3 to about 4.5 vol%, and as another example from about 3.5 to about 4.5 vol%, based on the total volume of the deprotecting composition (see [0017]). Therefore, the reference claims anticipate instant claims 1-8.
Regarding claim 9, reference claim 9 teaches the process wherein directing the first inert gas through the upper interior portion of the reaction, and directing a second inert gas into the lower interior portion of the reaction vessel. Additionally, reference claim 12 recites the first pressure of the first inert gas ranges from about 1 psi to about 25 psi and the second pressure of the second inert gas is less than the first pressure. This is in direct correlation with the instant application pressure ranges as specified as In some embodiments, the inert gas can be directed through the reaction vessel as an intermittent (e.g., pulsed) flow in some embodiments, inert gas directed into and/or flowing through the reaction vessel may have a pressure of about 1 psi to about 25 psi (see instant Specification page 32, 1st paragraph).
Regarding claim 10, reference claim 13, 35, and 70 recite the heating step comprises heating the protected amino acid and the deprotecting agent using microwave radiation; and the heating is conducted at a temperature from about 70°C to about 120°C; and the heating is conducted at a temperature from about 40°C to about 120°C
Regarding claim 11, reference specification states deprotecting reactions can be conducted at elevated temperatures, for example up to about 120°C, for example about 90°C to about 120°C, and as another example about 90°C to about 110°C, without limitation. Piperidine has a boiling point of about 106°C and pyrrolidine has a boiling point of about 87°C (see [0091]).
Regarding claim 12, reference claims 15, 52, 74, and 104 recite the deprotecting agent comprises pyrrolidine.
Regarding claims 13 and 14, reference claims 38-40 and 60-62 recite deprotecting agent in an amount from about 2 vol% to about 5 vol%; about 2 vol% to about 4.5 vol%; about 3 vol% to about 4.5 vol% based on the total volume of the deprotecting composition. Additionally, reference specification states that in some embodiments, the deprotecting composition may include the deprotecting agent in an amount of greater than about 5 vol%, for example, about 20 vol% or more, based on the total volume (100% volume) of the deprotecting composition. In some embodiments, the deprotecting composition may include the deprotecting agent in an amount from about 20 vol% to 100 vol%, for example from about 20 to about 50 vol%, for example from about 20 vol% to about 40 vol%, and as another example from about 20 to about 35 vol%, based on the total volume of the deprotecting composition (see [0071]).
Regarding claims 15-17, reference specification discloses solid supports comprising polyethylene glycol, polystyrene (see [0077]); use of a protecting group suitable for protection of amine or N-terminus includes without limitation a fluorenylmethyloxycarbonyl (Fmoc) (see [0074]); and 0.19 mmol/g substitution is used as the solid phase resin support (see [00184]).
Regarding claim 18, reference claims 21 and 24 discloses a portion of the volatized deprotecting agent condenses on the side wall, and the directing step further comprises directing the first inert gas towards the side wall to move condensed deprotecting agent downwardly towards the lower interior portion of the reaction vessel; and to remove a protecting group from the protected amino acid, wherein the deprotecting comprises: heating the first protected amino acid and a deprotecting agent in a lower interior portion of a reaction vessel during the deprotecting, wherein the heating evaporates deprotecting agent into an upper interior portion of the reaction vessel; and directing an inert gas into the upper interior portion of the reaction vessel through a first opening in an upper portion of the reaction vessel and out of the upper interior portion of the reaction vessel through a second opening in the upper portion of the reaction vessel during the heating to remove evaporated deprotecting agent from the interior of the reaction vessel during the deprotecting. Reference specification also discloses the solid phase peptide synthesis process of the present disclosure more specifically can include: deprotecting a first amino acid (e.g., removing a protecting group of a first protected amino acid), which first amino acid can be linked directedly or indirectly to a solid phase resin, to form a deprotected amino acid; optionally washing the deprotected amino acid; coupling a second amino acid to the deprotected amino acid to form a peptide from the first and second amino acids; and repeating the deprotecting, washing, and/or coupling steps to form a peptide comprising the first, second, and successive plurality of amino acids, wherein one or more of the deprotecting steps employ the inert gas purging (flushing) step described herein (e.g. in accordance with the first and/or second embodiments of the deprotection steps) (see [00128]).
Regarding claims 19-33, 35, and 36, reference claims 37, 41-43, 48, and 54 teaches a process for deprotecting a protected amino acid during solid phase peptide synthesis, comprising: removing a protecting group of a protected amino acid with a deprotecting composition; the deprotecting composition including a deprotecting agent in an amount of about 5 vol% or less based on the total volume of the deprotecting composition; venting the inert gas and evaporated deprotecting agent from the upper interior portion of the reaction vessel through an opening located in an upper portion of the reaction vessel; heating is conducted at a temperature from about 40°C to about 120°C; and continuously directing the inert gas through the interior of the reaction vessel during the step of removing the protecting group.
Regarding claim 34, reference claim 79 recites the process does not include a washing step after the deprotecting step and before the coupling step.
Regarding claim 37, reference claims 57, 63-65, 76, and 80-82 teaches the deprotecting comprising: removing a protecting group of the protected amino acid with a deprotecting composition including a deprotecting agent in an amount of about 5 vol% or less based on the total volume of the deprotecting composition; continuously directing the inert gas through the interior of the reaction vessel during the removing of the protecting group; further comprising washing the interior of the reaction vessel after the deprotection step and before the coupling step with solvent in an amount that is less than the total volume of the deprotecting composition; in an amount that is less than 1/2 of the total volume of the deprotecting composition; in an amount that is less than 1/3 of the total volume of the deprotecting composition. Additionally, reference specification teaches in some embodiments, the solid phase peptide synthesis process can include: deprotecting a first protected amino acid (e.g., removing a protecting group of a first protected amino acid) to form a deprotected amino acid; washing the deprotected amino acid; coupling a second amino acid to the deprotected amino acid to form a peptide from the first and second amino acids; and repeating the deprotecting, washing, and coupling steps to form a peptide comprising the first, second, and successive plurality of amino acids (see [00129]).
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to KOYELI BANERJEE whose telephone number is (571)272-5751. The examiner can normally be reached Monday-Friday 8-4PM.
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) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Melissa Fisher can be reached at (571) 270-7430. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/KOYELI BANERJEE/Examiner, Art Unit 1658
/Melissa L Fisher/Supervisory Patent Examiner, Art Unit 1658
Prosecution Insights