Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 9/14/26 has been entered.
Claims 1-20 are pending. Claims 2 and 4-20 remain withdrawn. As a result, claims 1 and 3 are being examined in this Office Action
Response to Amendment
Applicant’s amendments overcome the following objections and rejection. They are withdrawn.
The objections to claim 1 and to the disclosure for blurry schemes are withdrawn. The new schemes in claim 1 and in the substitute specification are clear. The superscripts can now be read.
The objection to claim 1 and the 112(b) rejection of claims 1 and 3 for the step labels are withdrawn. The steps in claim 1 are now labeled (a) through (i). These labels now match the steps in formula (A).
The written description concern in the advisory action mailed 9/2/26 is resolved for claim 1. Applicant deleted “water” from step (d) of formula (A) in claim 1. Step (d) of claim 1 now matches the original disclosure.
However, applicant did not make the same change in the substitute specification or in withdrawn claim 5. See the new matter objection and the notes on the withdrawn claims below. Also, since applicant filed an RCE, the examiner has reviewed the claims again as a whole. New objections and new rejections under 35 U.S.C. 112(b) are set forth below. The examiner has also set forth suggested claim language to help place the application in condition for allowance.
Specification
The substitute specification filed on 8/14/26 is objected to under 35 U.S.C. 132(a) because it introduces new matter into the disclosure. 35 U.S.C. 132(a) states that no amendment shall introduce new matter into the disclosure of the invention.
The added material which is not supported by the original disclosure is “water” in step (d). “Water” now appears in step (d) of formula (A) (substitute specification, page 6). “Water” also now appears in reaction formula (d) (substitute specification, page 12).
The original disclosure does not use water in step (d). The original reaction formula (d) lists a rhodium catalyst, a copper catalyst, an alkali, the second organic solvent, and air (or oxygen). It does not list water (original specification, page 10). Step (d) of the original formula (A) also does not list water (page 4). The text for step (d) also leaves out water (pages 3 and 11).
In contrast, the original text and schemes for steps (b) and (f) do list water (pages 3-4, 7-9, and 15-18). Also, Example 2 does not add water when S3 is combined with the catalysts, the allenol 5a, and THF (pages 28-29). Thus the original disclosure makes a clear distinction between the routes that use water and the route that does not.
Applicant has deleted “water” from step (d) in claim 1. But the same change was not made in the specification. Applicant is required to cancel the new matter in the reply to this Office action. Any new substitute specification must comply with 37 CFR 1.125.
Appropriate correction is required.
Objections
Claims 1 and 3 are objected to because of the following informalities:
Claim 1 is objected to because of the following:
a. “the first organic solvent” in step (a) and “the second organic solvent” in step (b) lack antecedent basis. At first use, they should read “a first organic solvent” and “a second organic solvent”.
b. Claim 1 names the same reagent two ways. Step (a) recites “bis[(pinacol)boryl]methane”. Step (e) recites “bis[(pinacol)boronyl]methane”. Applicant should use one name.
c. Step (d) has no subject of its own. As written, step (d) reads as if “the alkenyl boronate shown in said S2” is combined with the allenol. But formula (A) shows that S3 is combined with the allenol. The examiner suggests: “(d) the alkenyl boronic acid shown in S3 generated in said step (c) is combined with an allenol shown in 5 ...”.
d. Steps (b), (d), and (f) each recite “the allenol shown in 5”. This implies that the same allenol is used in each step. But formula (A) shows the allenol of step (f) with its own groups R2, Hc, and Hd. The examples also use different allenols in the two coupling steps (e.g., Examples 11 and 13). The examiner suggests “an allenol shown in 5” in each of steps (b), (d), and (f).
e. The Markush groups are not in proper alternative form. For example, “Ha is hydrogen, deuterium, tritium” should read “Ha is hydrogen, deuterium, or tritium”. The same applies to Hb, Hc, Hd, He, R1, and R2. Also, “heterocyclic” in R1 and R2 should read “heterocyclic group”.
f. “the vitamin derivative labeled with hydrogen isotope” lacks antecedent basis. It should read “the vitamin A derivative labeled with the hydrogen isotope”.
Claim 3 is objected to because “the third organic solvent” in step (2) lacks antecedent basis. At first use, it should read “a third organic solvent”.
Claim 3 also has the same Markush form issue as claim 1 (item e above).
Appropriate correction is required.
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.
Claims 1 and 3 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112, second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor regards as the invention.
The “aryl” group (claims 1 and 3). Claims 1 and 3 define the aryl group as “a phenyl group with substituent at the ortho, meta and para positions”. This is unclear. It can be read to require a substituent at each of the ortho, meta, and para positions or it can also be read to require a substituent at only one or more of these positions. These readings give very different scopes. Also, applicant’s Example 10 uses allenol 5d, which has a 4-tert-butylphenyl group. This phenyl group has a substituent only at the para position. Thus one of ordinary skill in the art would not know the metes and bounds of “aryl”. The examiner suggests: “said aryl group is a phenyl group having a substituent at one or more of the ortho, meta, and para positions, and said substituent includes ...”.
End steps (g), (h), and (i) (claim 1). The text of claim 1 requires all three end steps. Step (g) reduces compound 1 to compound 2. Step (h) esterifies compound 2 to compound 3. Step (i) oxidizes compound 1 to compound 4. But formula (A) shows compound 1 splitting into two branches. One branch is step (g) followed by step (h). The other branch is step (i). Formula (A) uses the same kind of branch for step (b) versus steps (c)-(d). The claim text recites those steps as alternatives (“or”). In addition, Examples 14, 15, and 16 each make only one end product. Thus it is unclear whether claim 1 requires all of steps (g), (h), and (i), or only one branch. The examiner suggests reciting the end steps as clear alternatives. See the suggested claim language below.
Zero amounts (claim 3). Claim 3 requires an alkali and water. They appear in reaction formula (b), in the text (“under the action of rhodium catalyst, copper catalyst, alkali, water”), and in step (1) (“putting rhodium catalyst, alkali, copper catalyst, compound S2, allenol 5, water and the second organic solvent into a dry reaction flask”). But the molar ratio in claim 3 allows the alkali to be zero (“0~0.60”) and the water to be zero (“0~20.0”) (last line of claim 3). A reagent cannot be both required and absent. Thus the scope of claim 3 is unclear. The examiner suggests a lower limit above zero for each. For example, applicant may recite the preferred ranges of the original specification for the alkali (0.20~0.30) and for the water (2.0~5.0) (original specification, page 9). Or applicant may recite “greater than 0 to 0.60” for the alkali and “greater than 0 to 20.0” for the water.
The dependent claim 3 is also rejected as depending upon a rejected claim. Appropriate correction is required.
Allowable Subject Matter
Claims 1 and 3 would be allowable if rewritten or amended to overcome the rejections under 35 U.S.C. 112(b) and the objections set forth in this office action. The new matter must also be cancelled from the specification.
The following is a statement of reasons for the indication of allowable subject matter:
Milas (Science, New Series, Vol. 103, No. 2680 (May 10, 1946), pp. 581-583) is the closest prior art. Milas teaches the synthesis of Vitamin A by condensation, substitution, dehydrogenation and hydrogenation as follows (page 582):
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However, Milas does not teach or suggest applicant’s total synthesis of vitamin A, especially the use of applicant’s allenol 5, as recited in claim 1. In applicant’s claimed method, β-cyclocitral (S1) reacts with bis[(pinacol)boryl]methane and LiTMP to give the alkenyl boronate S2. S2, or its boronic acid S3, is then coupled with allenol 5 under rhodium and copper catalysis in air or oxygen to give the 2-alkenal S4. S4 is converted to the alkenyl boronate S5. S5 is then coupled with allenol 5 in the same way to give the retinal compound 1. The key coupling step goes through a 1,4-hydrogen (or hydrogen isotope) transfer. This allows site-specific control of the number of deuterium atoms on the methyl groups of the polyene chain.
Withdrawn Claims – Rejoinder and Cancellation
Claims 2 and 4-10 are withdrawn. These claims depend from claim 1. If claim 1 becomes allowable, these claims will be considered for rejoinder. See MPEP 821.04. Rejoined claims must be fully examined for patentability. See 37 CFR 1.104. To speed allowance, the examiner notes the following issues in claims 2 and 4-10. Applicant is invited to correct them in the next reply.
a. Claim 5 – new matter. Reaction formula (d) in claim 5 now shows “water”. The original reaction formula (d) does not show water (original specification, page 10). Original claim 5 also does not show water (see PGPub US 2024/0166597, claim 5). The text of claim 5 does not recite water. This is the same new matter issue that applicant corrected in claim 1. “Water” should be deleted from reaction formula (d) in claim 5.
b. Claims 5 and 7 – zero amounts. Both claims require an alkali. Claim 7 also requires water. But the molar ratios allow zero alkali (“0~0.60”) and, in claim 7, zero water (“0~20.0”). This is the same issue as in claim 3. It should be corrected in the same way.
c. Claims 2 and 6 – LiTMP. Each claim states that LiTMP “is prepared by using 2,2,6,6-tetramethylpiperidine and N-butyllithium”. Step (1) of each claim also prepares LiTMP on site. But the ratio clause then states “if lithium 2,2,6,6-tetramethylpiperidide solution is prepared on site”. The word “if” suggests that on-site preparation is optional. The examiner suggests deleting the first molar ratio and the word “if”. Only the ratio for on-site preparation should remain.
d. Claims 8-10 – 35 U.S.C. 112(d). As now written, claim 1 already requires steps (g), (h), and (i). Claims 8, 9, and 10 only restate these steps. Thus they do not further limit claim 1. If claim 1 is amended to recite the end steps as alternatives (as suggested below), claims 8-10 would each select one branch. They would then further limit claim 1. Otherwise, claims 8-10 should be cancelled.
e. Other informalities.
“N-butyllithium” (claims 2 and 6) should read “n-butyllithium”. “obtaing” (claim 6) should read “obtaining”.
Claims 2 and 6 use both “boryl” and “boronyl” for the same reagent; one name should be used.
“the third organic solvent” (claims 5 and 7) should read “a third organic solvent” at first use.
“said reaction formula (e) specifically comprises” (claim 6) should read “said reaction shown in reaction formula (e) specifically comprises”.
“said functional group include” (claims 8 and 10) should read “said functional group includes”.
The “aryl” definition and the Markush form in claims 2 and 4-10 should be corrected in the same way as in claim 1.
Claims 11-20 should be cancelled. Claim 12 is drawn to compounds 1-4 as products. It is not a method claim that requires all the limitations of claim 1. Thus it is not eligible for rejoinder. Claims 11 and 13-20 each recite the “application of the method of claim [X] in the preparation of vitamin A and derivative thereof and deuterated compound thereof”. These claims recite a use without any active, positive steps. Such claims are indefinite under 35 U.S.C. 112(b) and are not a proper process under 35 U.S.C. 101. See MPEP 2173.05(q). They also add nothing to the methods of the claims from which they depend. Withdrawn claims that are not rejoined must be cancelled before allowance. Applicant is requested to cancel claims 11-20 in the next reply.
Examiner’s Suggested Claim Language
The examiner suggests the claim 1 language below. It would overcome the 112(b) rejections and the claim objections of record. Formula (A) should remain as presented on 9/14/26, with “water” deleted from step (d). This suggestion is made to advance prosecution. Applicant may choose other wording that is supported by the original disclosure.
1. A total synthesis method of vitamin A or a derivative thereof, wherein said total synthesis method comprises the following steps:
(a) the alkenyl boronate shown in S2 is produced from β-cyclocitral shown in S1 and bis[(pinacol)boryl]methane (
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) under the action of lithium tetramethylpiperidide (LiTMP) in a first organic solvent;
then either step (b), or step (c) followed by step (d):
(b) the 2-alkenal shown in S4 is produced from the alkenyl boronate shown in S2 generated in said step (a) and an allenol shown in 5 under the action of a rhodium catalyst, a copper catalyst, an alkali, water, and air or oxygen in a second organic solvent; or
(c) the alkenyl boronate shown in S2 generated in said step (a) is hydrolyzed into the alkenyl boronic acid shown in S3, and
(d) the alkenyl boronic acid shown in S3 generated in said step (c) is combined with an allenol shown in 5 under the action of a rhodium catalyst, a copper catalyst, an alkali, and air or oxygen in a second organic solvent to produce the 2-alkenal shown in S4;
(e) the alkenyl boronate shown in S5 is produced from the 2-alkenal shown in S4 generated in said step (b) or (d) and bis[(pinacol)boryl]methane (
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) under the action of LiTMP in the first organic solvent;
(f) the retinal or the retinal with substituent shown in 1 is produced from the alkenyl boronate shown in S5 generated in said step (e) and an allenol shown in 5 under the action of a rhodium catalyst, a copper catalyst, an alkali, water, and air or oxygen in the second organic solvent; and
after said step (f), at least one of the following is carried out:
(g) the retinal or the retinal with substituent shown in 1 generated in said step (f) is subjected to a reduction reaction to produce the vitamin A or the vitamin A with substituent shown in 2, and optionally (h) the vitamin A or the vitamin A with substituent shown in 2 generated in said step (g) is subjected to an esterification reaction to produce the vitamin A ester or the vitamin A ester with substituent shown in 3; and
(i) the retinal or the retinal with substituent shown in 1 generated in said step (f) is subjected to an oxidation reaction to produce the vitamin A acid or the vitamin A acid with substituent shown in 4;
wherein, when the allenol shown in 5 used in said step (b), (d), and/or (f) is labeled with a hydrogen isotope, the vitamin A or the vitamin A derivative obtained is labeled with the hydrogen isotope;
the synthetic route of said total synthesis method is shown in the following formula (A):
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wherein,
Ha is hydrogen, deuterium, or tritium;
R1 is hydrogen, deuterium, tritium, phenyl, aryl, a heterocyclic group, a hydrocarbyl group, or a hydrocarbyl group with a functional group;
Hb is hydrogen, deuterium, or tritium;
Hc is hydrogen, deuterium, or tritium;
R2 is hydrogen, deuterium, tritium, phenyl, aryl, a heterocyclic group, a hydrocarbyl group, or a hydrocarbyl group with a functional group;
Hd is hydrogen, deuterium, or tritium;
He is hydrogen, deuterium, or tritium;
R3 is an acyl group;
wherein said aryl group is a phenyl group having a substituent at one or more of the ortho, meta, and para positions, and said substituent includes alkyl, alkenyl, phenyl, halogen, trifluoromethyl, alkoxy, alkoxycarbonyl, acyl, acyloxy, amido, sulfonyl, sulfonyloxy, hydroxyl, nitro, carboxy, cyano, and amino groups; said heterocyclic group refers to a 3-10-membered heterocyclic ring whose ring atoms are carbon, nitrogen, oxygen, or sulfur, which is an aliphatic ring, an aromatic ring, or a ring formed by combining two or more simple rings; and in said hydrocarbyl group with a functional group, said functional group includes acyl, hydroxyl, halogen, alkoxy, alkoxycarbonyl, formyl, acyloxy, amido, sulfonyl, sulfonyloxy, nitro, carboxy, and cyano groups.
For claim 3, the examiner suggests the following changes:
(1) recite “a third organic solvent” at first use in step (2);
(2) recite a lower limit above zero for the alkali and the water at the claim’s last line, for example: “the molar ratio of said rhodium catalyst, copper catalyst, alkali, compound S2, allenol 5, and water is (0.005~0.10):(0.005~1.20):(0.20~0.30):(1.0~3.0):1.0:(2.0~5.0)”; and
(3) correct the “aryl” definition and the Markush form as in claim 1.
If applicant adopts the language above, cancels the new matter from the specification, and cancels claims 11-20, the application would appear to be in condition for allowance. Withdrawn claims 2 and 4-10 would then be considered for rejoinder, if corrected as noted above. Applicant is invited to call the examiner to discuss any of these issues.
Conclusion
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jennifer Cho Sawyer whose telephone number is (571) 270 1690. The examiner can normally be reached on Monday-Friday 9 AM - 6 PM PST.
If attempts to reach the examiner by telephone are unsuccessful, the examiner's supervisor, Renee Claytor can be reached on (571) 272-8394. The fax phone number for the organization where this application or proceeding is assigned is 571-274-1690.
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/JENNIFER C SAWYER/Examiner, Art Unit 1691
/RENEE CLAYTOR/Supervisory Patent Examiner, Art Unit 1691
