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 .
Claims 1-19 are pending.
Applicant’s election without traverse of a method for the preparation of a bioconjugate that read on (A)/(C) a cyclic alkyne (Q30) (i.e., a bicyclo[6.1.0]non-4-yn-9- yl] (BCN) group):
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as the species of alkyne/click probe Q, (B) an azide as the specie of click probe F, (D) an exatecan (a camptothecin) as the cytotoxin payload, and (E) an antibody as the biomolecule in the reply filed on December 22, 2025 is acknowledged.
Claims 10-11 are withdrawn from further consideration by the examiner, 37 C.F.R. 1.142(b) as being drawn to non-elected inventions.
Claims 1-9 and 12-19, drawn to a method for the preparation of a bioconjugate of structure B-(Z-L-D)x that read on (A)/(C) a cyclic alkyne (Q30) (i.e., a bicyclo[6.1.0]non-4-yn-9- yl] (BCN) group):
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as the species of alkyne/click probe Q, (B) an azide as the specie of click probe F, (D) an exatecan (a camptothecin) as the cytotoxin payload, and (E) an antibody as the biomolecule, are being acted upon in this Office Action.
Priority
Receipt is acknowledged of papers submitted under 35 U.S.C. 119(a)-(d), which papers have been placed of record in the file.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on December 22, 2025 has been considered by the examiner and an initialed copy of the IDS is included with this Office Action.
Drawings
The drawings filed on March 1, 2023 are acceptable.
Specification
The lengthy specification has not been checked to the extent necessary to determine the presence of all possible minor errors. Applicant's cooperation is requested in correcting any errors of which applicant may become aware in the specification.
Claim Objections
Claims 1, 4-7, 9 are objected to because of the following informality: the dash “-“ should have been “to”.
Claim 3 is objected to because of the following informality: “and” is missing between “(SDS)” and “sodium deoxycholate”.
Claim 9 is objected to because of the following informality: the multiple “R15 may be linked together” at page 4, 5, 6 should have been “R15 is linked together”.
Claim 13 is objected to because of the following informalities:
the plural alkaloids, anthracyclines, camptothecins, taxanes, calicheamycins, tubulysins, irinotecans, duocarmycins, maytansines, auristatins, enediynes, pyrrolobenzodiazepines (PBDs) or indolinobenzodiazepine dimers (IGN) and derivatives should have been singular.
multiple “or” should be deleted.
“selected from” should have been “selected from the group consisting of”.
Claim 14 is objected to because of the following informality: “is selected from…or…” should have been “is elected from the group consisting of…and…”.
Claim 15 is objected to because of the following informality: the plural proteins, glycoproteins, antibodies, polypeptides, peptides, glycans, lipids, nucleic acids, oligonucleotides, polysaccharides, oligosaccharides, enzymes, hormones, amino acids and monosaccharides should be singular.
Claim 16 is objected to because of the following informalities:
the plural affimers, atrimers, bicyclic peptides and tricyclic peptides should be singular.
adnectin/centryin should be adnectins, centryin.
Claim Rejections - 35 USC § 112
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 6 and 9 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which applicant regards as the invention.
Claim 6 recites “the concentration” in claim 1. There is insufficient antecedent basis for this limitation in the claim. Amending claim 6 to recite “…wherein the molecule is in the range of 1 to 100 mg/ml” would obviate this rejection.
Claim 9 recites the limitations "the (hetero)cycloalkynyl moiety Q" at page 4, and “cycloocynyl moiety Q” at p. 5 in claim 1. There is insufficient antecedent basis for this limitations in the claim.
Claim rejections under - 35 U.S.C. 112
The following is a quotation of 35 U.S.C. 112(a):
(a) IN GENERAL.—The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same, and shall set forth the best mode contemplated by the inventor or joint inventor of carrying out the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), first paragraph:
The specification shall contain a written description of the invention, and of the manner and process of making and using it, in such full, clear, concise, and exact terms as to enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the same and shall set forth the best mode contemplated by the inventor of carrying out his invention.
Claims 1-9 and 12-19 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, as failing to comply with the written description requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to reasonably convey to one skilled in the relevant art that the inventor or a joint inventor, or for pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The Written Description Guidelines for examination of patent applications indicates, “the written description requirement for a claimed genus may be satisfied through sufficient description of a representative number of species by actual reduction to practice, or by disclosure of relevant, identifying characteristics, i.e., structure or other physical characteristics and/or other chemical properties, by functional characteristics coupled with a known or disclosed correlation between function and structure, or by a combination of such identifying characteristics, sufficient to show applicant was in possession of the claimed genus.” (see MPEP 2163).
The claims are drawn to a method for the preparation of a bioconjugate of structure B-(Z-L-D),comprising reacting:
(i) an alkyne or alkene compound of structure Q-L-D, wherein
(a) Q is a click probe comprising a cyclic alkyne moiety or a cyclic alkene moiety,
(b) L is a linker, and
(c) D is any payload; with
(ii) a molecule of structure B-(F)x, wherein
(a) B is a biomolecule that is functionalized with x click probes F;
(b) F is a click probe capable of reacting with Q, and
(c) x is an integer in the range of 1 - 10, in presence of any surfactant, to form a bioconjugate wherein the payload is covalently attached to the biomolecule via connecting group Z that is formed by a click reaction between Q and F, any surfactant contains a negative charged moiety such as sodium decanoate, sodium dodecanoate, sodium lauryl sulfate (SDS), sodium deoxycholate, in any solvent system containing water and organic solvent in a ratio in the range of 50/50 to 100/0 or 72/25 to 95/5 wherein the click probe Q comprises a cyclic alkyne moiety and the click probe F is an azide and the drug is any cytotoxin such as camptothecins or any derivatives thereof, the biomolecule is any antibodies, such as any mAb, Fab, VHH, scFv, diabody, or minibody.
Claim 1 recites a method for the preparation of a bioconjugate of structure B-(Z-L-D),comprising reacting:
(i) an alkyne or alkene compound of structure Q-L-D, wherein
(a) Q is a click probe comprising a cyclic alkyne moiety or a cyclic alkene moiety,
(b) L is a linker, and
(c) D is any payload; with
(ii) a molecule of structure B-(F)x, wherein
(a) B is a biomolecule that is functionalized with x click probes F;
(b) F is a click probe capable of reacting with Q, and
(c) x is an integer in the range of 1 - 10, in presence of any surfactant, to form a bioconjugate wherein the payload is covalently attached to the biomolecule via connecting group Z that is formed by a click reaction between Q and F.
Claim 2 recites the method according to claim 1, wherein the surfactant contains a negatively charged moiety.
Claim 3 recites the method according to claim 1, wherein the surfactant is selected from the group consisting of sodium decanoate, sodium dodecanoate, sodium lauryl sulfate (SDS), and sodium deoxycholate.
Claim 4 recites the method according to claim 1, wherein the reaction is performed in a solvent system containing water and organic solvent in a ratio in the range of 50/50 - 100/0.
Claim 5 recites the method according to claim 4, wherein the reaction is performed in a solvent system containing water and organic solvent in a ratio in the range of 75/25 - 95/5.
Claim 6 recites the method according to claim 1, wherein the concentration of the molecule of structure is in the range of 1 - 100 mg/ml.
Claim 7 recites the method according to claim 6, wherein the concentration of the molecule of structure is in the range of 5 - 50 mg/ml.
Claim 8 recites the method according to claim 1, wherein the click probe Q comprise a cyclic alkyne moiety and click probe F is azide.
Claim 9 recites the method according to claim 1, wherein the click probe Q is
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.
Claim 12 recites the method according to claim 1, wherein the payload D is a cytotoxin.
Claim 13 recites the method according to claim 12, wherein the cytotoxin is camptothecins or doxorubicin.
Claim 15 recites the method according to claim 1, wherein the biomolecular is antibodies.
Claim 16 recites the method according to claim 15, wherein the biomolecular is mAb.
Claim 17 recites the method according to claim 1, wherein the click probe F is connected to a monosaccharide moiety.
Claim 18 recites the method according to claim 17, wherein the click probe F is connected to a terminal monosaccharide moiety of a glycan of an antibody.
Claim 19 recites a method of preparing a bioconjugate having structure B-(Z-L-D)x, wherein x payloads D are covalently attached to a biomolecule B via connecting group Z, the method comprising click reacting click probe Q with click probe F in presence of a surfactant, wherein the reaction is between:
(i) an alkyne or alkene compound of structure Q-L-D, wherein
(a) Q is a click probe comprising a cyclic alkyne moiety or a cyclic alkene moiety,
(b) L is a linker, and
(c) D is a payload; with
(ii) a molecule of structure B-(F)x, wherein
(a) B is a biomolecule that is functionalized with x click probes F;
(b) F is a click probe capable of reacting with Q, and
(c) x is an integer in the range of 1 - 10, wherein:
(i) the conversion of the bioconjugation reaction is increased;
(ii) the yield of the bioconjugation reaction is increased;
(iii) the amount of organic co-solvent is reduced in the solvent system wherein the bioconjugation reaction is performed;
(iv) flexibility in the concentration of biomolecule during the bioconjugation reaction is increased;
(v) the excess of alkyne- or alkene-functionalized payload used during the bioconjugation reaction is reduced;
(vi) the extent of aggregate formation during the bioconjugation reaction is reduced;
(vii) downstream processing of the bioconjugate is simplified; and/or
(viii) the drug-to-antibody ratio (DAR) of the bioconjugate is improved, compared to the same reaction in absence of a surfactant.
The specification discloses:
Example 1
Synthetic Preparation
[0221] Compounds X1 and X2 were prepared according to Verkade et al., Antibodies 2018, 12, doi:10.3390/antib7010012. Compounds X5A, X9 and X10 were prepared according to WO 2019/110725 (respectively compounds 150, 140 and 157). Compound X6 was prepared according to WO 2018/146189 (compound 4). Compound X8 was prepared according to WO 2017/137457 (compound 56). Compounds X11 and X12 were prepared according to WO 2021/144313 (respectively compounds 137 and 304).
Example 2
Enzymatic Remodeling of Rituximab to Rituximab-(6-N3-GaINAc).SUB.2
[0222] Rituximab (15 mg/mL) was incubated with EndoSH (1% w/w), as described in PCT/EP2017/052792 (WO 2017/137459), His-TnGaINAcT, described in PCT/EP2016/059194 (WO 2016/170186) (5% w/w) and UDP 6-N3-GaINAc (25 eq compared to IgG), prepared according to PCT/EP2016/059194 (WO 2016/170186) in TBS containing 10 mM MnCl2 for 16 hours at 30° C. Next, the functionalized IgG was purified using a HiTrap MabSelect Sure 5 mL column. After loading of the reaction mixture the column was washed with TBS +0.2% Triton and TBS. The IgG was eluted with 0.1 M glycine-HCI pH 2.7 and neutralized with 1 M Tris-HCI pH 8.8. After three times dialysis to PBS, the IgG was concentrated to 15-20 mg/mL using a Vivaspin Turbo 15 ultrafiltration unit (Sartorius).
Example 3
Enzymatic Remodeling of Trastuzumab to Trastuzumab-(6-N3-GaINAc).SUB.2
[0223] Trastuzumab (15 mg/mL) was incubated with EndoSH (1% w/w), as described in PCT/EP2017/052792 (WO 2017/137459), His-TnGaINAcT, described in PCT/EP2016/059194 (WO 2016/170186) (5% w/w) and UDP 6-N3-GaINAc (25 eq compared to IgG), prepared according to PCT/EP2016/059194 (WO 2016/170186) in TBS containing 10 mM MnCl2 for 16 hours at 30° C.
[0224] Next, the functionalized IgG was purified using a HiTrap MabSelect Sure 5 mL column. After loading of the reaction mixture the column was washed with TBS +0.2% Triton and TBS. The IgG was eluted with 0.1 M glycine-HCI pH 2.7 and neutralized with 1 M Tris-HCI pH 8.8. After three times dialysis to PBS, the IgG was concentrated to 15-20 mg/mL using a Vivaspin Turbo 15 ultrafiltration unit (Sartorius).
Example 4
Screening different Surfactants at 10 mg/mL Antibody Concentration
[0225] Rituximab-(6-N3-GaINAc).sub.2 (10 mg/mL, 0.2 mg) was incubated overnight with compound X1 or compound X2 (0.125-0.2 mM (2-3 equiv.) with 10% DMF. Optionally, sodium deoxycholate (11 mM), sodium decanoate (37.5 mM) or CHAPS (12 mM) were added. After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the drug:antibody ratio (DAR). Results are depicted in FIG. 6.
Example 5
Comparison at 15 mg/mL and 10% DMF with compound X1 (structure in FIG. 7A)
[0226] Rituximab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.2 mg) was incubated overnight with X1 (0.26 mM, 3 equiv.) with 10% DMF and optionally sodium decanoate (37.5 mM) or sodium deoxycholate (11 mM) were added. After 16 h, reactions were analyzed with RP-HPLC analysis (after reduction) to determine the DAR. Results are depicted in the Table below.
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Example 6
Comparison at 15 mg/mL and 10% DMF with compound X2 (structure in FIG. 7A)
[0227] Rituximab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.2 mg) was incubated overnight with X2 (0.3 mM, 3 equiv.) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-HPLC analysis (after reduction) to determine the DAR. Results are depicted in the Table below.
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Example 7
Conjugation with X2 in Propylene Glycol (PG)
[0228] Trastzumab-(6-N3-GaINAc).sub.2 (10 mg/mL, 0.2 mg) was incubated overnight with X2 0.4 mM (6 equiv.) or 0.33 mM (5 equiv.) with 30% PG and either no additive or 11 mM sodium deoxycholate. After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the DAR.
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Example 8
Comparison at 15-10 mci/mL and 5% DMF with compound X1
[0229] Trastuzumab-(6-N3-GaINAc).sub.2 (10-15 mg/mL, 0.2 mg) was incubated overnight with X1 (0.2-0.3 mM , 3 equiv) with 5% DMF and sodium deoxycholate (22 mM) were added. After 16 h, reactions was analyzed with RP-HPLC analysis (after reduction) to determine the DAR. Results are depicted in the Table below.
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Example 9
Conjugation with X2 in Propylene Glycol (PG)
[0230] Trastzumab-(6-N3-GaINAc).sub.2 (10 mg/mL, 0.2 mg) was incubated overnight with X2 0.33 mM (5 equiv) with 20-25-30% PG and 11-22 mM sodium deoxycholate. After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the DAR.
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Example 10
Comparison at 15 mci/mL and 10% DMF with compound X5A
[0231] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.3 mg) was incubated overnight with X5A (2 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the DAR. Results are depicted in the Table below. A clear improvement in DAR is noted in case sodium deoxycholate is used during conjugation.
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Example 11
Comparison at 10 mci/mL and 10% DMF with compound X6
[0232] Trastuzumab-(6-N3-GaINAc).sub.2 (10 mg/mL, 0.3 mg) was incubated overnight with X6 (2 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (after DTT reduction) to determine the DAR. Results are depicted in the Table below. A clear improvement in DAR is noted in case sodium deoxycholate is used during conjugation.
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Example 12
Comparison at 15 mci/mL and 10% DMF with compound X8
[0233] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.3 mg) was incubated overnight with X8 (2 or 3 equiv vs. antibody) with 10% DMF and optionally CHAPS (12 mM), sodium deoxycholate (11 mM) or sodium decanoate (37.5 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (after DTT reduction) to determine the drug-to-antibody ratio (DAR). Results are depicted in the Table below. A great improvement in DAR is noted in case sodium deoxycholate or sodium decanoate are used during conjugation.
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Example 13
Comparison at 15 mci/mL and 10% DMF with compound X9
[0234] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.3 mg) was incubated overnight with X9 (2 or 3 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (after DTT reduction) to determine the DAR. Results are depicted in the Table below. A great improvement in DAR is noted in case sodium deoxycholate is used during conjugation.
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Example 14
Comparison at 15 mci/mL and 10% DMF with compound X10
[0235] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 0.3 mg) was incubated overnight with X10 (2 or 3 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (after DTT reduction) to determine the DAR.
[0236] Results are depicted in the Table below. A clear improvement in DAR is noted in case sodium deoxycholate is used during conjugation.
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Example 15
Comparison at 5 mci/mL and 10% DMF with compound X11
[0237] Trastuzumab-(6-N3-GaINAc).sub.2 (5 mg/mL, 0.3 mg) was incubated overnight with X11 (1.5 or 2.5 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (after DTT reduction) to determine the DAR, and RP-UPLC analysis (intact samples) to determine relative amounts of “DARO” (unconjugated antibody), “DAR1” (closed DAR1 conjugate, where two click reactions have occurred between both azido moieties of a single antibody and both BCN moieties of a single compound X11; and open DAR1 conjugates, where only click reaction has occurred between an azido moiety and a BCN moiety) and “DAR2” conjugates (where both azido moieties of a single antibody have reacted with two BCN moieties of different compounds X11). Results are depicted in the Table below. A clear improvement in %DAR1 is noted in case sodium deoxycholate is used during conjugation.
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Example 16
Comparison at 5 mg/mL and 10% DMF with compound X12
[0239] Trastuzumab-(6-N3-GaINAc).sub.2 (5 mg/mL, 0.3 mg) was incubated overnight with X12 (1.5 or 2.5 equiv vs. antibody) with 10% DMF and optionally sodium deoxycholate (11 mM) was added. After 16 h, reactions were analyzed with RP-UPLC analysis (intact samples after quenching with 1-azidomethylpyrene) to determine relative amounts of “DARO” (unconjugated antibody), “DAR1” (closed DAR1 conjugate, where two click reactions have occurred between both azido moieties of a single antibody and both BCN moieties of a single compound X12) and “other” conjugates (open DAR1 conjugates, where only click reaction has occurred between an azido moiety and a BCN moiety; and DAR2 conjugates where both azido moieties of a single antibody have reacted with two BCN moieties of different compounds X12). Results are depicted in the Table below. A clear improvement in %DAR1 is noted in case sodium deoxycholate is used during conjugation.
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Example 17
Conjugation of Trastuzumab-(6-N3-GaINAc).SUB.2 .with Compound X1 in the Absence of Sodium Deoxycholate (comparative)
[0240] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 7 mg) was incubated overnight with X1 (7 equiv) with 25% DMF. After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the DAR (3.7). Subsequently, the reaction was diluted to 2.5 mL with TBS and subsequent concentrated to 1 mL using amicon 10 kDa spinfilters, and then purified on an AKTA Purifier-10 (GE Healthcare) with a Superdex200 Increase 10/300 GL (GE Healthcare) column to yield the conjugate in 80% yield.
Example 18
Conjugation of Trastuzumab-(6-N3-GaINAc).SUB.2 .with compound X1 in the presence of Sodium Deoxycholate
[0241] Trastuzumab-(6-N3-GaINAc).sub.2 (15 mg/mL, 10 mg) was incubated overnight with X1 (3 equiv) with 10% DMF and sodium deoxycholate (11 mM). After 16 h, reactions were analyzed with RP-HPLC analysis (after DTT reduction) to determine the DAR (3.7). Subsequently, the reaction was directly purified on an AKTA Purifier-10 (GE Healthcare) with a Superdex200 Increase 10/300 GL (GE Healthcare) column to yield the conjugate in 89% yield.
[0242] The results of examples 17 and 18 show that the presence of the surfactant provides a higher yield. Also, the downstream processing (work-up, purification) of the conjugate after the conjugation reaction is simplified, as the dialysis step with amicon 10 kDa spinfilters was not needed for the conjugation reaction in the presence of surfactant.
Other than the azido modified trastuzumab (Trastuzumab-(6-N3-GaINAc) conjugated to various compounds X1 to X2, X5A, X6, X9, X10, X11, X12 or propylene glycol (PG) in the presence of sodium deoxycholate (11 or 22 mM) or sodium decanoate (37.5 mM) and 5 or 10% DMF, the specification does not describe the method set forth in claim 1 in the presence of any surfactant such as dodecanoate, dodecyl sulfate (e.g. SDS), 3-[(3-cholamidopropyl)dimethylammonio]-1-propanesulfonate (CHAPS) and 3-[(3-cholamidopropyl)dimethylammonio]-2-hydroxy propanesulfonate (CHAPSO) wherein the reaction is perform in a solvent system comprising water and any organic solvent in ratio ranging from 50/50 to 100/0 or 75/25 to 95/5.
Regarding any molecule of structure B-(F)x wherein B is any biomolecule, any biomolecule such as any antibodies (claim 15), any mAb, any Fab, VHH, scFv, diabody, minibody (claim 16) that is functionalized with any x click probes F capable reacting with any Q and x is an integer of 1-10, the specification discloses just one azide functional trastuzumab.
However, one species of azido modified trastuzumab (Trastuzumab-(6-N3-GalNAc) is not representative of the genus of any click probe F functionalized biomolecule (claim 1) or antibodies (claim 15) such as any mAb, any Fab, any VHH, any scFv, any diabody, any minibody functionalized with any x click probes F (claim 16) that capable of reacting with any click probe Q modified linker payload encompassed by the claimed method. When there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. The specification does not disclose any relevant, identifying characteristics, such as chemical structure of any and all biomolecule, e.g., proteins, glycoproteins, peptides, glycans, lipids, nucleic acids, oligonucleotide, polysaccharides, oligosaccharide, enzymes, hormones, amino acids or monosaccharides functionalized with any x click probes F (claim 1, 15) or the structure, e.g., immunoglobulin heavy and light chain variable domains of all antibodies such as any mAb, any Fab, any VHH, any scFv, any diabody, any minibody functionalized with any x click probes F (claim 16). The specification fails to disclose a correlation between structure and function, e.g., binding specificity of the antibody. The specification does not describe the structure common to member of the genus so the one of skill in the art can visualize or recognize the member of the genus of the actual biomolecule that is functionalized with x click probes F that react with any alkyne or alkene compound functionalized with any click probe linker and payload in the presence of any surfactant encompassed by the claimed method.
It is known in the art that antibodies have a large repertoire of distinct structures and that a huge variety of antibodies can be made to bind to a single epitope.
For example, Lloyd et al. taught that hundreds of functional antibody fragments can be isolated from an antibody library that bind to the same antigen wherein these antibodies have distinct heavy and light chain sequences (Lloyd et al. Protein Engineering, Design & Selection 22:159-168, 2009; PTO 892; see, e.g., Discussion).
Similarly, Edwards et al., (J Mol Biol. 334(1): 103-118, 2003; PTO 892) found that over 1000 antibodies, all different in amino acid sequence, were generated to a single protein; 568 different amino acid sequences identified for the V(H) CDR3 domains of these antibodies (Abstract).
Poosarla et al (Biotechn. Bioeng., 114(6): 1331-1342, 2017; PTO 892) teach substantial diversity in designed mAbs (sharing less than 75% sequence similarity to all existing natural antibody sequences) that bind to the same 12-mer peptide, binding to different epitopes on the same peptide. Said reference further teaches “most B-cell epitopes... in nature consist of residues from different regions of the sequence and are discontinuous...de novo antibody designs against discontinuous epitopes present additional challenges...". (See entire reference.)
Nejadmoghaddam (Avicenna Journal of Medical Biotechnology 2(1): 3-23, 2019; PTO 892) discusses major obstacles of antibody-drug conjugates include off-target toxicity, tumor marker selection, antibody specificity, adequately affinity and receptor-mediated internalization are major aspects of choice, cytotoxic payload (e.g., up to 7 drugs per antibody), cytotoxic payload linkage strategy, aqueous solubility, non-immunogenic and stability in storage and bloodstream, see entire document, abstract, p. 15, in particular.
Thus, the application at best describes a roadmap for producing various combinations of alkyne or alkene compound of any click probe comprising a cyclic alkyne moiety or cyclic alkene moiety linker and payload and any click probe F functionalized with any biomolecule or antibodies in the presence of any surfactant and then determining which actually form a bioconjugate as claimed.
“A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when ... the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004).
Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that “applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the written description inquiry, whatever is now claimed.” (See page 1117.) The specification does not “clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed.” (See Vas-Cath at page 1116.).
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016.
One cannot describe what one has not conceived. See Fiddles v. Baird, 30 USPQ2d 1481, 1483. In Fiddles v. Baird, claims directed to mammalian FGF’s were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Thus, the specification fails to describe these DNA sequences.
For genus claims, an adequate written description of a claimed genus requires more than a generic statement of an invention's boundaries. A patent must set forth either a representative number of species falling within the scope of the genus or structural features common to the members of the genus. Kubin, Exparte, 83 USPQ2d 1410 (Bd. Pat. App. & Int. 2007); Ariad Pharms., Inc. v. Eli Lilly& Co., 598 F.3d 1336, 1350 (Fed. Cir. 2010).
Therefore, only a method for the preparation of a bioconjugate comprising reacting azido functionalized Trastuzumab-(6-N3-GalNAc) with a bicyclo(6,1,0)non-4-yne (BCN)-linker-payload wherein the BCN-linker-payload comprises a BCN functionalized with a linker sulfamide PEG or val-cit-PABC and the payload is monomethyl auristatin E (MMAE) or duocarmycin SA in the presence of sodium deoxycholate or sodium decanoate, but not the full breadth of the claims meets the written description provision of 35 U.S.C. § 112, first paragraph. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 U.S.C. § 112 is severable from its enablement provision (see page 1115).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103(a) which forms the basis for all obviousness rejections set forth in this Office action:
(a) A patent may not be obtained though the invention is not identically disclosed or described as set forth in section 102 of this title, if the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains. Patentability shall not be negatived by the manner in which the invention was made.
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(a) are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims under pre-AIA 35 U.S.C. 103(a), the examiner presumes that the subject matter of the various claims was commonly owned at the time any inventions covered therein were made absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and invention dates of each claim that was not commonly owned at the time a later invention was made in order for the examiner to consider the applicability of pre-AIA 35 U.S.C. 103(c) and potential pre-AIA 35 U.S.C. 102(e), (f) or (g) prior art under pre-AIA 35 U.S.C. 103(a).
Claims 1-3, 8-9 and 12-19 are rejected under 35 U.S.C. 103 as being unpatentable over WO2014065661 publication (published May 1, 2014; PTO 892) in view of Schneider et al (Bioorganic & Medicinal Chemistry 24: 995-1001, 2016; PTO 892).
Claim 1 recites a method for the preparation of a bioconjugate of structure B-(Z-L-D),comprising reacting:
(i) an alkyne or alkene compound of structure Q-L-D, wherein
(a) Q is a click probe comprising a cyclic alkyne moiety or a cyclic alkene moiety,
(b) L is a linker, and
(c) D is any payload; with
(ii) a molecule of structure B-(F)x, wherein
(a) B is a biomolecule that is functionalized with x click probes F;
(b) F is a click probe capable of reacting with Q, and
(c) x is an integer in the range of 1 - 10, in presence of any surfactant, to form a bioconjugate wherein the payload is covalently attached to the biomolecule via connecting group Z that is formed by a click reaction between Q and F.
Claim 2 recites the method according to claim 1, wherein the surfactant contains a negatively charged moiety.
Claim 3 recites the method according to claim 1, wherein the surfactant is selected from the group consisting of sodium decanoate, sodium dodecanoate, sodium lauryl sulfate (SDS), and sodium deoxycholate.
Claim 8 recites the method according to claim 1, wherein the click probe Q comprise a cyclic alkyne moiety and click probe F is azide.
Claim 9 recites the method according to claim 1, wherein the click probe Q is
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.
Claim 12 recites the method according to claim 1, wherein the payload D is a cytotoxin.
Claim 13 recites the method according to claim 12, wherein the cytotoxin is camptothecins or doxorubicin.
Claim 15 recites the method according to claim 1, wherein the biomolecular is antibodies.
Claim 16 recites the method according to claim 15, wherein the biomolecular is mAb.
Claim 17 recites the method according to claim 1, wherein the click probe F is connected to a monosaccharide moiety
Claim 18 recites the method according to claim 17, wherein the click probe F is connected to a terminal monosaccharide moiety of a glycan of an antibody.
Claim 19 recites a method of preparing a bioconjugate having structure B-(Z-L-D)x, wherein x payloads D are covalently attached to a biomolecule B via connecting group Z, the method comprising click reacting click probe Q with click probe F in presence of a surfactant, wherein the reaction is between:
(i) an alkyne or alkene compound of structure Q-L-D, wherein
(a) Q is a click probe comprising a cyclic alkyne moiety or a cyclic alkene moiety,
(b) L is a linker, and
(c) D is a payload; with
(ii) a molecule of structure B-(F)x, wherein
(a) B is a biomolecule that is functionalized with x click probes F;
(b) F is a click probe capable of reacting with Q, and
(c) x is an integer in the range of 1 - 10, wherein:
(i) the conversion of the bioconjugation reaction is increased;
(ii) the yield of the bioconjugation reaction is increased;
(iii) the amount of organic co-solvent is reduced in the solvent system wherein the bioconjugation reaction is performed;
(iv) flexibility in the concentration of biomolecule during the bioconjugation reaction is increased;
(v) the excess of alkyne- or alkene-functionalized payload used during the bioconjugation reaction is reduced;
(vi) the extent of aggregate formation during the bioconjugation reaction is reduced;
(vii) downstream processing of the bioconjugate is simplified; and/or
(viii) the drug-to-antibody ratio (DAR) of the bioconjugate is improved, compared to the same reaction in absence of a surfactant.
Regarding claim 1, the WO2014065661 publication teaches a process for the preparation of an antibody-conjugate, see p. 35. The process comprises reacting or conjugating
(i) alkyne compound of structure Q-L-D, e.g., linker-conjugates wherein (a) is a click probe, e.g., BCN, (B) L is a linker, e.g., val-cit-PABA and (C) a payload such as a cytotoxin, e.g., doxorubicin (Examples 4, 6) or MMAE or MMAF (example 9), Figure 10a, with
(ii) a molecule of structure B-(F)x such as azide-modified antibody (p. 33, line 17), wherein (a) B is an antibody, e.g., trastuzumab (example 13-15), (b) F is a click probe, e.g., azide, that capable of reacting with Q, e.g., alkynyl group, heterocycloakynyl group or cyclooctyne probe via a cycloaddition reaction, (c) x is 2 to 4, see Examples 15-7, 24, in particular.
Regarding claim 8-9, the WO2014065661 publication teaches that the click probe Q is a cyclic alkyne moiety such as the BCN moiety having the structure
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The click probe F is an azide (aka N3), see p. 25, line 7.
Regarding claims 12-14, the WO2014065661 publication teaches that the drug is a cytotoxin, see p. 36, line 18. Examples of cytotoxins include camptothecins, doxorubicin, daunorubicin, taxanes, calicheamycins, duocarmycins, maytansines and maytansinoids (i.e. maytansine derivatives), auristatins or pyrrolobenzodiazepines (PBDs Examples of cytotoxins include camptothecins, staurosporin, doxorubicin, daunorubicin, colchicine, methotrexate, taxanes, calicheamycins, duocarmycins, maytansines and maytansinoids (i.e. maytansine derivatives), auristatins, tubulysin M, cryptophycin or pyrrolobenzodiazepines (PBDs). Examples of auristatins include dolastatin 10, auristatin F, monomethyl auristatin F (MMAF), auristatin E, monomethyl auristatin E (MMAE), auristatin PE, auristatin TP and auristatin AQ. Examples of maytansines and maytansinoids include mertansine and ansamitocin, see p. 36.
Regarding claims 15-16, the WO2014065661 publication teaches that the antibody is a monoclonal antibody trastuzumab (Examples 10), bevacizumab (Example 11), cetuximab (Example 12), or rituximab (Example 12-1), p. 17, in particular. Examples of antibody include monoclonal antibody, Fab, scFv, diabody, minibody, see p. 17, line 1-18.
The publication teaches that when an azide-modified antibody according to the invention is coupled to a linker-conjugate comprising an alkynyl group, or when an alkyne modified antibody according to the invention is coupled to a linker-conjugate comprising an azide moiety, via a cycloaddition reaction, the resulting triazoles are not susceptible to hydrolysis or other degradation pathways. Additional advantages are thus the stability of antibody-conjugates according to the invention, as well as the straightforward and generally applicable process for the introduction of an azido group, a keto group or an alkynyl group into an antibody, see p. 9, in particular.
Regarding claim 18, the WO2014065661 publication teaches that the click probe F, e.g., BCN is connected to a terminal monosaccharide moiety of a glycan, e.g., a terminal non-reducing GlcNAc of an antibody, see p. 6, line 8, or the terminal GlcNAc-S(A)x wherein GlcNAc is an N-acetylglucosamine, wherein S(A)x is a sugar, see p. 7, Fig. 3-4, abstract or UDP-GalNAz via copper-catalyzed conjugation with alkyne-biotin, see p. 11, p. 17, Figures 15, 17. Examples of terminal monosaccharide include 6-azidofucose (6-AzFuc), see p. 26.
The WO2014065661 publication does not teach the process is performed in the presence of a surfactant as per claim 1 wherein the surfactant contains a negatively charged moiety as per claim 2, wherein the surfactant is sodium lauryl sulfate (SDS) as per claim 3.
However, Schneider teaches anionic (aka negative charged) surfactants, e.g., Sodium dodecyl sulfate (SDS) enhances click reaction-mediated protein conjugation. Claim 3 is included because the reference sodium dodecyl sulfate (SDS) is the same as instant sodium lauryl sulfate (SDS) which 12-carbon. Examples of click reaction includes copper (Cu I) catalyzed alkyne and azide cycloaddition (CuAAC), see entire document, Table 1. The yield of click reaction between ubiquitin (Ub G76Aha) and Pol beta K61Plk increased up to about 70% while N-lauroylsacrsine increased the yield up to about 100%, see Table 1. Schneider teaches that the effect of negatively charged surfactants on click reaction can be generalized to other surfactant such as SDS and NLS, see p. 987, right col. This is specifically observed with surfactants that exhibit both, a negatively charged head group and an alkane chain of sufficient length, see p. 998, in particular. Schneider further teaches that the optimal reaction conditions have to be determined for each protein pair studied by titration of the respective surfactant. Importantly, for the proteins tested, the concentrations of detergent that efficiently enhance conjugation are non-denaturing and do not interfere with protein folding and function, see p. 998, left col., in particular.
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to include Schneider’s negative charged surfactant such as Sodium dodecyl sulfate (SDS) in the method of preparation of bioconjugate via cycloaddition of the WO2014065661 publication in order to increase the yield of the conjugate as taught by Schneider. Claim 19 is included as Schneider teaches the yield of click reaction for conjugation increased in the presence of a surfactant.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to modify the method of the WO2014065661 publication in view of Schneider et al because Schneider teaches that negative charge surfactants or detergent can efficiently enhance conjugation and are non-denaturing and do not interfere with protein folding and function, see p. 998, left col., in particular.
One of ordinary skill in the art would have been motivated to do so because the WO2014065661 publication teaches that click chemistry, specifically azide-alkyne cycloaddition has become a key method for producing homogenous, site-specific ADCs with improved stability, pharmacokinetics and therapeutic index, see p. 68-69.
Further, “The combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results.” KSR Int’l Co. v. Teleflex Inc., 550 U.S. 398, 416 (2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Claims 4-7 are rejected under 35 U.S.C. 103 as being unpatentable over WO2014065661 publication (published May 1, 2014; PTO 892) in view of Schneider et al (Bioorganic & Medicinal Chemistry 24: 995-1001, 2016; PTO 892) as applied to claims 1-3, 8-9 and 12-19 mentioned above and further in view of Zhao et al (US20150322155, published November 12, 2015; PTO 892) and Van Berkel (US20190038765, published February 7, 2019; PTO 892).
Claim 4 recites the method according to claim 1, wherein the reaction is performed in a solvent system containing water and organic solvent in a ratio in the range of 50/50 - 100/0.
5. (Original) The method according to claim 4, wherein the reaction is performed in a solvent system containing water and organic solvent in a ratio in the range of 75/25 - 95/5.
6. (Currently Amended) The method according to claim 1, wherein the concentration of the molecule of structure is in the range of 1 - 100 mg/ml.
7. (Currently Amended) The method according to claim 6, wherein the concentration of the molecule of structure is in the range of 5 - 50 mg/ml.
The combine teachings of the WO2014065661 publication and Schneider have been discussed supra.
The references do not teach that the reaction is performed in a water and organic solvent in a ratio in the range of 50/50 to 100/0 as per claim 4, or water to organic solvent in a ratio in the range of 72/25 to 95/5 as per claim 5, wherein the concentration of the molecule of azido modified antibody is in the range of 1 to 100 mg/ml as per claim 6 or in the range of 5 to 50 mg/ml as per claim 8.
However, Zhao teaches that typically, a small percentage of organic co-solvents may be required to add to the reaction mixture in order to achieve higher conjugation yield of the alkyne group on the bridge linkers and the antibody. Examples co-solvents include water and organic solvent such as methanol, ethanol, dimethyl formamide (DMF), dimethyl acetamide (DMA) or dimethysulfoxide (DMSO), see para. [0096]. Examples of aqueous media with or without addition of 0 to about 30% organic solvent, such as DMA, DMF, ethanol, methanol, acetone to introduce the reactive groups containing azide to the cell-binding agent, e.g., antibody through the click chemistry, see para. [0089] to [0090].
Zhao teaches that typically, the antibody is dissolved in an aqueous buffer at 1 to 35 mg/ml, which is within the claimed range of 1 to 100 as per claim 6 or 5 to 50 mg/ml as per claim 7, see para. [0096].
Likewise, van Berkel teaches the controlled attachment of a distinct number of toxic payloads to a monoclonal antibody is key, with a payload typically selected from the group of auristatins, maytansinoids, duocarmycins, enediynes or pyrrolobenzodiazepines (PBDs), with many others are underway. With the exception of auristatin F, all toxic payloads are poorly soluble or water-insoluble, which necessitates organic co-solvents to achieve successful conjugation, such as 25% N,N-dimethylacetamide (DMA) or dimethylformamide (DMF) or up to 50% propylene glycol (PG). In case of hydrophobic payloads, despite the use of aforementioned co-solvents, large stoichiometries of reagents may be required during conjugation while efficiency and yield may be significantly compromised due to aggregation, see para. [0008]. Van Berkel further teaches a first advantages of the process for the preparation of a bioconjugate as described herein, and of the linker-conjugates and sulfamide linker according to the invention is that conjugation efficiency increases in case a sulfamide linker is used instead of a typical polyethylene glycol (PEG) spacer. An additional advantage of a sulfamide group, in particular of an acylsulfamide or a carbamoylsulfamide group, is its high polarity, which imparts a positive effect on the solubility of a linker comprising such group, and on the construct as a whole, before, during and after conjugation. In view of this increased polarity, conjugation with first precursor containing the sulfamide linker according to the invention are particularly suited to conjugate hydrophobic target compounds to a biomolecule. The high polarity of the sulfamides also has a positive impact in case hydrophobic moieties are conjugated to a biomolecule of interest, which is known to require large amounts of organic co-solvent during conjugation and/or induce aggregation of the bioconjugate. High levels of co-solvent (up to 50% of DMA, DMF, or DMSO) may induce protein denaturation during the conjugation process and/or may require special equipment in the manufacturing process. Thus, the problem of aggregation associated with the hydrophobic linking moieties in bioconjugates is efficiently solved by using the sulfamide linker according to the invention in the spacer between the target molecule and the reactive group Q.sup.1 in the linker-conjugate in the formation of the bioconjugate. An additional advantage of a sulfamide linker according the invention, and its use in bioconjugation processes, is its ease of synthesis and high yields, see para. [0419].
In view of the combined teachings of the references, it would have been prima facie obvious to a person of ordinary skill in the art before the effective filling date of the claimed invention to prepare antibody conjugate of the WO2014065661 publication and Schneider by including Zhao’s
co-solvent such as water and organic solvent such as methanol, ethanol, dimethyl formamide (DMF), dimethyl acetamide (DMA) or dimethysulfoxide (DMSO) in the range of 0 to about 30% or van Berkel’s cosolvent by adding 25% (aka 72/25) N,N-dimethylacetamide (DMA) or dimethylformamide (DMF) or up to 50% (aka 50/50) propylene glycol (PG) in water in order to achieve successful conjugation given some of toxic payloads are poorly soluble in water.
One of ordinary skill in the art would have had an expectation of success at the time the invention was made to perform the reaction in water and organic solvent ratio in the range of 75/25 up to 70/30 because Zhao teaches that organic solvent such as DMA, DMF, ethanol, methanol or acetone is typically added to the water ranging from 0 to about 30% during conjugating process and van Berkel teaches that higher levels of co-solvent DMA, DMF or DMSO up to 50% may induce protein denaturation during the conjugation process and/or may require specifical equipment in the manufacturing process, see para. [0419].
One of ordinary skill in the art would have had a reasonable expectation of success in using co-solvents such as water and methanol, ethanol, dimethyl formamide (DMF), dimethyl acetamide (DMA) or dimethysulfoxide (DMSO) because the solvent system typically imparts a positive effect on the solubility of some hydrophobic cytotoxic drugs, as taught by van Berkel and to achieve higher conjugation yield of the alkyne group on the bridge linkers and the antibody.
Consistence with the teachings of the specification, “Typical co-solvents for conjugation are DMSO, propylene glycol (PG), ethanol, DMF, DMA and NMP, which facilitate solubilization of linker-drug but can also mix well with water. Typical amount of co-solvent is 10-25% versus aqueous medium, however, co-solvents may be added up to 50% in some cases. Adding high amount of co-solvent is particularly favorable for conjugation processes where the payload is significantly hydrophobic (lipophilic) and in those processes where a large excess of linker-drug is required to achieve full conversion to desired product”, see para. [0019].
"[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum of workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233,235-236 (C.C.P.A. 1955). "No invention is involved in discovering optimum ranges of a process by routine experimentation." Id. at 458, 105 USPQ at 236-237. The "discovery of an optimum value of a result effective variable in a known process is ordinarily within the skill of the art." In re Boesch, 617 F.2d 272, 276, 205 USPQ 215,218-219 (C.C.P.A. 1980). MPEP 2144.05.
In addition, the claims would have been obvious because "a person of ordinary skill has good reason to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense". See KSR International Co. v. Teleflex Inc., 82 USPQ2d 1385 (U.S. 2007).
“The test of obviousness is not express suggestion of the cl aimed invention in any or all of the references but rather what the references taken collectively would suggest to those of ordinary skill in the art presumed to be familiar with them.” See In re Rosselet 146 USPQ 183, 186 (CCPA 1965).
“There is no requirement (under 35 USC 103(a)) that the prior art contain an express suggestion to combine known elements to achieve the claimed invention. Rather, the suggestion to combine may come from the prior art, as filtered through the knowledge of one skilled in the art.,” Motorola, Inc, v. Interdigital Tech. Corn., 43 USPQ2d 1481, 1489 (Fed. Cir. 1997).
Accordingly, the claimed invention as a whole was prima facie obvious to one of ordinary skill in the art before the effective filling date of the claimed invention especially in the absence of evidence to the contrary.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to PHUONG HUYNH whose telephone number is (571)272-0846. The examiner can normally be reached on 9:00 a.m. to 6:30 p.m. The examiner can also be reached on alternate alternative Friday from 9:00 a.m. to 5:30 p.m.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Misook Yu, can be reached at 571-270-3497. The fax phone number for the organization where this application or proceeding is assigned is 571-272-0839.
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/PHUONG HUYNH/ Primary Examiner, Art Unit 1641