DETAILED ACTION
Notice of AIA Status
The instant application, filed on or after 16 March 2013, is being examined under the first inventor to file provisions of the Leahy-Smith America Invents Act (AIA ).
Status of the Claims
The listing of claims filed 1 February 2024 has been reviewed.
New claims 1–19 are pending.
Priority
The instant application is a continuation of U.S. Pat. App. Serial No. 16/623,052, filed 16 December 2019 (now U.S. Pat. No. 11,781,164); a national stage application of PCT/EP2018/066155, filed 18 June 2018, and claims priority to Denmark PA201770473, filed 16 June 2017. Applicant’s claim for foreign priority is acknowledged, and a copy of the priority document was received in U.S. Pat. App. Serial No. 16/623,052.
Information Disclosure Statement
The information disclosure statement (IDS) submitted on 30 October 2023 is acknowledged and has been considered.
Objections to the Specification
The abstract of the disclosure is objected to because it recites phrases that can be implied (“The invention relates to”) and legal phraseology (“comprising”).
Appropriate correction is required.
Examiner recommends, in the first line, deleting “The invention relates to” and capitalizing “recombinant.”
For guidelines for the preparation of patent abstracts, see MPEP § 608.01(b) (Explaining: The abstract should be in narrative form and avoid legal phraseology (e.g., means, said), terms referring to purported merits of the invention (e.g., new, novel), and phrases that can be implied (e.g., The disclosure concerns, The disclosure defined by this invention). The language should be clear and concise, and not repeat information given in the title. It should not compare the invention with the prior art. The abstract is generally limited to a single paragraph within the range of 50 to 150 words in length.).
Claim Rejections - 35 U.S.C. § 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.
(i) Claims 1–19 are rejected under 35 U.S.C. § 112(b) 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.
Each of independent claims 1 and 15–18 requires a step of contacting thebaine,
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, and/or oripavine,
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, with a recombinant host cell that expresses one or more genes encoding a cytochrome P450 enzyme capable of N-demethylating and/or O-demethylating the thebaine and/or the oripavine to produce a compound of formula (II), shown below.
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The phrase “and/or” is interpreted to mean “and” or in the alternative “or.” Based on the use of “or,” only one of N-demethylating and/or O-demethylating the substrate is required.
Both thebaine and oripavine have an N-methyl group, as shown above, and the methyl group must be N-demethylated to an N-H group to provide the compound of formula (II). As such, the claim is internally inconsistent because the N-demethylating of thebaine and/or oripavine cannot be optional as is currently recited in the claim. In other words, it is unclear how the compound of formula (II) is prepared if the thebaine and/or oripavine is only O-demethylated and not also N-demethylated.
Claims 2–14 and 19 depend from one of claims 1 or 15–18 without curing the deficiency.
Appropriate correction is required.
(ii) Claim 3 is rejected under 35 U.S.C. § 112(b) 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.
Claim 3 depends from claim 1.
Claim 1 recites, “reacting the compound of formula (II) with . . . benzyl sulfonate” and “reacting the compound of formula (III) with . . . benzyl sulfonate.”
Claim 3 recites, “wherein sulfonate group is . . .”
An independent claim introduces subject matter for the first time and commonly recites the indefinite article “a.” A dependent claim referring back to prior claim and to the same subject matter should recite the definite article “the.” Such formal claim drafting provides proper antecedent basis for the claimed subject matter and avoids ambiguity, therefore improving the clarity of the claims.
In this case, claim 1 twice recites “benzyl sulfonate” – the first time without the indefinite article “a” and the second time without the definite article “the.” Claim 3 refers to “sulfonate group” without either article and different words. Due to the lack of articles in both claims and the different terms used in claim 3, it is unclear what “sulfonate group” is referring to.
It is unclear whether the latter recitation(s) of the terms refer to the former recitations or permit separate components. Appropriate correction is required.
Claim Rejections - 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.
Claims 1–18 are rejected under 35 U.S.C. § 112(a) as failing to comply with the written description requirement. The claims contain subject matter that was not described in the Specification in such a way as to reasonably convey to one of ordinary skill in the art that Applicant, at the time the application was filed, had possession of the claimed invention.
In Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1351 (Fed. Cir. 2010) (en banc), the Federal Circuit stated “the hallmark of written description is disclosure.” A specification adequately describes an invention when it “reasonably conveys to those skilled in the art the inventor had possession of the claimed subject matter as of the filing date.” (Id.). “A ‘mere wish or plan’ for obtaining the claimed invention is not adequate written description.” Centocor Ortho Biotech, Inc. v. Abbott Labs., 636 F.3d 1341, 1348 (Fed. Cir. 2011).
What is required to meet the written description requirement “varies with the nature and scope of the invention at issue, and with the scientific and technologic knowledge already in existence.” Capon v. Eshhar, 418 F.3d 1349, 1357 (Fed. Cir. 2005). In Ariad, the Federal Circuit explained what is required to meet the written description requirement:
This inquiry, as we have long held, is a question of fact. Ralston Purina, 772 F.2d at 575. Thus, we have recognized that determining whether a patent complies with the written description requirement will necessarily vary depending on the context. Capon v. Eshhar, 418 F.3d 1349, 1357–58 (Fed. Cir. 2005). Specifically, the level of detail required to satisfy the written description requirement varies depending on the nature and scope of the claims and on the complexity and predictability of the relevant technology. Id. For generic claims, we have set forth a number of factors for evaluating the adequacy of the disclosure, including “the existing knowledge in the particular field, the extent and content of the prior art, the maturity of the science or technology, [and] the predictability of the aspect at issue.” Id. at 1359.
(Ariad, at 1351).
The written description of a genus, such as a chemical genus, “requires a precise structure, formula, [or] chemical name” of the claimed subject matter sufficient to distinguish it from other materials. Regents of the Univ. of Cal. v. Eli Lilly & Co., 199 F.3d 1559, 1568 (Fed. Cir. 1997). The Federal Circuit commented on that case in the Ariad decision:
We held that a sufficient description of a genus instead requires the disclosure of either a representative number of species falling within the scope of the genus or structural features common to the members of the genus so that one of skill in the art can “visualize or recognize” the members of the genus. Id. at 1568-69. We explained that an adequate written description requires a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials. Id. at 1568 (quoting Fiers v. Revel, 984 F.2d 1164, 1171 (Fed. Cir. 1993)). We have also held that functional claim language can meet the written description requirement when the art has established a correlation between structure and function. See Enzo, 323 F.3d at 964 (quoting 66 Fed. Reg. 1099 (Jan. 5, 2001)). But merely drawing a fence around the outer limits of a purported genus is not an adequate substitute for describing a variety of materials constituting the genus and showing that one has invented a genus and not just a species.
(Ariad, at 1350).
The factors outlined in the above Federal Circuit cases are analyzed with respect to the claimed invention in turn below.
(A) The nature and scope of the claim invention in view of the specification: the claimed invention relates generally to the chemical and pharmaceutical arts and more specifically to methods of synthesizing opiates comprising a step of contacting thebaine and/or oripavine with a recombinant host cell that expresses one or more genes encoding a cytochrome P450 enzyme capable of N-demethylating and/or O-demethylating the thebaine and/or the oripavine.
The instant specification states the demethylation step “is one of the most critical in the synthesis.” (Spec., p.1).
The specification states: “Without knowing the gene sequence and thereby the amino acid sequence of the enzymes responsible for the demethylation reactions such expressions in heterologous hosts is not possible.” (Id., p.2).
The specification states: “Before the present invention, it was not known which type of enzyme was responsible for the N-demethylation reaction in fungi of the Mucorales order and sequences of the responsible enzymes not isolated. Filamentous fungi can like plants typically have more than hundred Cytochrome P450 and dioxygenase enzymes, which could all be candidates for being N-demethylases.” (Id.).
The specification explains the recombinant host cell can be a yeast, plant, mammalian, insect, fungal, algal, or bacterial cell. (Id., p.42). The specification lists dozens of species from several of those categories of cells. (Id., pp.42–50). As noted, a fungi or plant species may contain multiple Cytochrome P450 and dioxygenase enzymes.
Based on the statements in the specification and the immense number of host cell species from which recombinant host cells could be derived, one of ordinary skill in the art would expect there to be thousands or millions of recombinant host cell candidates capable of facilitating the claimed N-demethylation reaction.
Table 1 of the specification discloses a list of less than 90 gene sequences derived from less than 50 species of cells. (Id., pp.165–166).
The claims define the host cell by its function and do not limit it by structure. As such, the claims cover thousands or millions of recombinant host cells capable of the function.
(B) The extent and content of the prior art: The specification explains that N-demethylation has previously been accomplished with fungi, human CYP3A4 and CYP3A5, and variants of P450 MB3 from Bacillus megaterium. (Id., p.2).
(C) The maturity of the science or technology: while methods of N-demethylating thebaine and/or the oripavine are known in the prior art, as acknowledged in the instant specification, the claimed method of using recombinant host cells for N-demethylating thebaine and/or the oripavine in combination with additional synthetic steps appears to be in its infancy.
(D) The predictability of the aspect at issue: the chemical and pharmaceutical arts are generally recognized as unpredictable. In re Fisher, 427 F.2d 833, 839 (CCPA 1970). The more unpredictable an area is the more specific disclosure is necessary to satisfy the statutory requirement. In this case, there is no evidence suggesting the claimed invention is more predictable than the chemical and pharmaceutical arts are generally.
The question of written description
When the above factors and the evidence of record are considered as a whole, the specification does not adequately describe a representative number of species to support the claimed invention to a method of N-demethylating and/or O-demethylating thebaine and/or oripavine using a recombinant host cell that expresses one or more genes encoding a cytochrome P450 enzyme capable of N-demethylating and/or O-demethylating the thebaine and/or the oripavine because: the specification discloses less than 100 examples of gene sequences compared to the disproportionate number of gene sequence candidates encompassed by the scope of the claim; the claimed syntheses are in an infant stage relative to the prior art; and the claimed syntheses, particularly the most critical step of demethylating the N-methyl substrates, are generally unpredictable in nature. Accordingly, based on a totality of evidence, the specification would not reasonably convey to those skilled in the art that the inventor had possession of a representative number of examples to support the full scope of syntheses as claimed.
Examiner recommends amending each independent claims to define the recombinant host cells as those listed in claim 19.
Conclusion
No claims are allowed.
Communication
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Jason Nolan at (571) 272-2480. The examiner can normally be reached Monday through Friday between 9:00–5:00.
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/J.M.N./Patent Examiner, Art Unit 1623
/ADAM C MILLIGAN/Supervisory Patent Examiner, Art Unit 1623
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