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 .
Application and Claims Status
Applicant’s preliminary amendments filed on January 23, 2024 are acknowledged and entered.
Claims 1-15 were pending. In the amendment as filed on January 23, 2024, applicants have amended claims 1, and 4-9; cancelled no claims; and added no new claims. Therefore, claims 1-15 are currently pending. Additionally, the present specification and abstract have been amended to conform to U.S. patent practice.
Priority
The instant application is a National Stage entry from International Application No. PCT/KR2022/011913, filed August 10, 2022, which claims priority to the benefit of Korean Patent Application Nos. 10-2021-0106106 filed on August 11, 2021, and 10-2022-0099674 filed on August 10,
2022 in the Korean Intellectual Property Office.
Information Disclosure Statement
The information disclosure statements (IDS) filed on 10/31/2024 and 12/10/2024 are in compliance with the provisions of 37 CFR 1.97. All references have been considered except where marked with a strikethrough. A signed copy of Form 1449 is included with this Office Action.
The information disclosure statement filed 1/23/2024 fails to comply with 37 CFR 1.98(a)(2), which requires a legible copy of each cited foreign patent document; each non-patent literature publication or that portion which caused it to be listed; and all other information or that portion which caused it to be listed. It has been placed in the application file, but the information referred to therein has not been considered.
The following issues have been noted with the listed documents on IDS submitted 1/23/2024, and thus, they have not been considered:
On IDS submitted 1/23/2024, the non-patent literature “Ribo, J.M. et al” only contains the cover page of the document (abstract only) and not the entire article.
On IDS submitted 1/23/2024, the non-patent literature “Boiadjiev S.E. et al” only contains the cover page of the document (abstract only) and not the entire article.
On IDS submitted 1/23/2024, the Office action issue on March 27, 2023 from Korean Patent Office is incoherently translated and thus, not readable.
The information disclosure statement filed 1/06/2025 fails to comply with 37 CFR 1.98(a)(3)(i) because it does not include a concise explanation of the relevance, as it is presently understood by the individual designated in 37 CFR 1.56(c) most knowledgeable about the content of the information, of each reference listed that is not in the English language. It has been placed in the application file, but the information referred to therein has not been considered.
On IDS submitted on 1/06/2025, the foreign patent document JP-2010-523532 has no explanation of relevance.
On IDS submitted on 1/06/2025, the foreign patent document JP-2024-531164 has no explanation of relevance
Claim Interpretation
In claims 1-15, Applicant recites the method for synthesizing bilirubin, shown by a genus structure as a compound of Formula 3 in claim 1. Applicant has not provided any explicit definition of bilirubin that is contrary to the industry standard. It is noted that, on page 65, line 8, Applicant recites “Compound F-3a (bilirubin)” and the symmetrical compound F-3a is depicted on page 51 (and elsewhere). However, this is not an explicit definition. Therefore, the broadest reasonable interpretation to the term “bilirubin” is being applied, where the industry standard is a compound of the structure shown below, and provided by Brower et al. (“Synthesis of a New Lipophilic Bilirubin. Conformation, Transhepatic Transport and Glucuronidation”, published 2000, cited in IDS filed on 01/23/2024) (hereinafter “Brower 2000”):
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Claims 2 and 3 recite the use of polyethylene glycol (PEG) reacting with compounds of Formula 1 or 3. Applicant does not disclose a definition of PEG, and the specification only discloses, on page 14-15, para [111]-[112], that “Polyethylene glycol is, for example, mPEGn-NH2 (methoxy polyethylene glycol-amine, n=5 to 60). Herein, n is the number of -CH2-CH2-O- repeating units of methoxy polyethylene glycol-amine, which may range from 5 to 60, 10 to 50, 10 to 40, 20 to 40, 10 to 30, or 20 to 30”. Applicant has not provided any explicit definition of PEG, and their provided example is a non-standard example of polyethylene glycol, which is commonly expressed as H-(O-CH2-CH2-)n-OH instead of mPEGn-NH2. Thus, Examiner is applying the broadest reasonable interpretation of PEG to mean H-(O-CH2-CH2-)n-OH, as applied to claims 2 and 3.
Specification – Abstract
Applicant is reminded of the proper content of an abstract of the disclosure.
A patent abstract is a concise statement of the technical disclosure of the patent and should include that which is new in the art to which the invention pertains. The abstract should not refer to purported merits or speculative applications of the invention and should not compare the invention with the prior art.
If the patent is of a basic nature, the entire technical disclosure may be new in the art, and the abstract should be directed to the entire disclosure. If the patent is in the nature of an improvement in an old apparatus, process, product, or composition, the abstract should include the technical disclosure of the improvement. The abstract should also mention by way of example any preferred modifications or alternatives.
Where applicable, the abstract should include the following: (1) if a machine or apparatus, its organization and operation; (2) if an article, its method of making; (3) if a chemical compound, its identity and use; (4) if a mixture, its ingredients; (5) if a process, the steps.
Extensive mechanical and design details of an apparatus should not be included in the abstract. The abstract should be in narrative form and generally limited to a single paragraph within the range of 50 to 150 words in length.
In chemical patent abstracts for compounds or compositions, the general nature of the compound or composition should be given as well as its use, e.g., “The compounds are of the class of alkyl benzene sulfonyl ureas, useful as oral anti-diabetics.” Exemplification of a species could be illustrative of members of the class. For processes, the type of reaction, reagents and process conditions should be stated, generally illustrated by a single example unless variations are necessary.
The abstract of the disclosure is objected to because the it does not sufficiently adhere to the contents of a chemical abstract around an improved process. If the patent is in the nature of an improvement in an old process, the abstract should include the technical disclosure of the improvement. For a chemical process, the reagents and conditions should be stated, generally illustrated by a single example. Furthermore, in the current Abstract, “Formula 1”, “Formula 2”, and “Formula 3” do not readily refer to any structure to allow a reader to quickly glean the nature of the patent. Last, the phrase “usefully used” is redundant. A corrected abstract of the disclosure is required and must be presented on a separate sheet, apart from any other text. See MPEP § 608.01(b) for guidelines for the preparation of patent abstracts.
Specification – Drawings
Acknowledgement is made of the drawings received 1/23/2024.
The drawings are objected to because:
In FIG. 1, the image is blurry, especially with regards to the numbering of the carbon atoms (as an example, the carbon presumably labeled “8”). In FIG. 3, the text along the axes is blurry and illegible. As recited in 37 CFR 1.84:
(l) Character of lines, numbers, and letters. All drawings must be made by a process which will give them satisfactory reproduction characteristics. Every line, number, and letter must be durable, clean, black (except for color drawings), sufficiently dense and dark, and uniformly thick and well-defined. The weight of all lines and letters must be heavy enough to permit adequate reproduction. This requirement applies to all lines however fine, to shading, and to lines representing cut surfaces in sectional views. Lines and strokes of different thicknesses may be used in the same drawing where different thicknesses have a different meaning.
In FIG. 1, the reference characters used to annotate the atoms of Compound F-3a are not mentioned in the description and thus should not appear in the drawings. As recited in 37 CFR 1.84:
(p) Numbers, letters, and reference characters.
(5) Reference characters not mentioned in the description shall not appear in the drawings. Reference characters mentioned in the description must appear in the drawings.
Corrected drawing sheets in compliance with 37 CFR 1.121(d) are required in reply to the Office action to avoid abandonment of the application. Any amended replacement drawing sheet should include all of the figures appearing on the immediate prior version of the sheet, even if only one figure is being amended. The figure or figure number of an amended drawing should not be labeled as “amended.” If a drawing figure is to be canceled, the appropriate figure must be removed from the replacement sheet, and where necessary, the remaining figures must be renumbered and appropriate changes made to the brief description of the several views of the drawings for consistency. Additional replacement sheets may be necessary to show the renumbering of the remaining figures. Each drawing sheet submitted after the filing date of an application must be labeled in the top margin as either “Replacement Sheet” or “New Sheet” pursuant to 37 CFR 1.121(d). If the changes are not accepted by the examiner, the applicant will be notified and informed of any required corrective action in the next Office action. The objection to the drawings will not be held in abeyance.
Specification – Disclosure
The specification is objected to for the following reasons:
The following images are blurry, and specifically, the R group numbering is illegible: Formula 1, para [9]; Formula 2, para [11]; Formula 6, para [19]; Formula 8, para [23]; Formula 11, para [27]; Formula 6, para [125].
On page 6, para [49], FIG. 1 is described as 2D NMR data of Compound F-3a. FIG. 1 is, in fact, not a 2D NMR spectrum, but rather a version of Compound F-3a where the atoms are numbered.
The 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 of the errors of which applicant may become aware of in the specification.
Claim Rejections - 35 USC § 112(b)
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 1-15 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 the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
A broad range or limitation together with a narrow range or limitation that falls within the broad range or limitation (in the same claim) may be considered indefinite if the resulting claim does not clearly set forth the metes and bounds of the patent protection desired. See MPEP § 2173.05(c). In the present instance, claim 1 recites the broad recitation of variables of the compound of Formula 3 outside those of the discrete structure of bilirubin, and the claim also recites “bilirubin”, which is the narrower statement of the range/limitation. In the instant case, claim 1 is drawn to a method of synthesizing bilirubin. However, the bilirubin Markush structure—encompassed by Formula 3, where R1 is H, R2 is H, R3 is a vinyl group, and R4 is H, also recites variables for R1-R4 that are beyond the scope of bilirubin. The claim(s) are considered indefinite because there is a question or doubt as to whether the feature introduced by such narrower language is (a) merely exemplary of the remainder of the claim, and therefore not required, or (b) a required feature of the claims.
As claims 2-9, 11-15 depend on claim 1 and do not resolve the present issue, they are also rejected.
Where applicant acts as his or her own lexicographer to specifically define a term of a claim contrary to its ordinary meaning, the written description must clearly redefine the claim term and set forth the uncommon definition so as to put one reasonably skilled in the art on notice that the applicant intended to so redefine that claim term. Process Control Corp. v. HydReclaim Corp., 190 F.3d 1350, 1357, 52 USPQ2d 1029, 1033 (Fed. Cir. 1999). The term “bilirubin” in claim 1 is used by the claim to mean “mesobilirubin,” while the accepted meaning is “bilirubin.” The term is indefinite because the specification does not clearly redefine the term. (See Claim Interpretation Section). Therefore, the metes and bounds of the instant application are unclear, as the Applicant is claiming bilirubin, but the structures are not bilirubin. Claims 2-15, which depend on claim 1, are also rejected as vague for not resolving the present issue of claim 1.
Claim 2 is rejected to as vague for reciting “further comprising reacting the compound represented by Formula 3 with polyethylene glycol (PEG)”. It is not clear where PEG is being reacted on the compound of Formula 3: if R3 is a vinyl group, is PEG added across the double bond; or, is PEG alcohol made into an appropriate leaving group and substituted onto the pyrrole nitrogen; or is PEG added into the pendant ester to make a PEGylated ester? If PEG is added to form a PEGylated ester, is the mono-PEGylated or bis-PEGylated ester formed? There are many options. Appropriate clarification is required.
Claim 3 is rejected as vague for reciting “the compound represented by Formula 1 is reacted with polyethylene glycol (PEG)”. Again, there are multiple sites where PEG can react on a compound of Formula 2 (i.e. the aldehyde or the ester), and the option for both the mono-PEGylated or bis-PEGylated ester is still unclear. Regardless of which site is chosen, the PEGylated compound of Formula 2 can be then coupled with the compound of Formula 1. Appropriate clarification is required.
Claim 4 is rejected as vague for reciting “X is an arylalkyl ester group having 8 to 20 carbons”. It is unclear if the 8-20 carbon limitation is solely for the arylalkyl portion of “arylalkyl ester”, or includes the “ester” carbonyl in the carbon count. So, for instance, does a benzyl ester have 7 carbon atoms (6 for the benzene, 1 for the methylene), or does it have 8 carbon atoms (6 for the benzene, 1 for the methylene, and 1 for the carbonyl)? Appropriate correction is required.
Claim 7 recites the limitation "the hydroxyl group". There is insufficient antecedent basis for this limitation in the claim, and it should properly read “a hydroxyl group”.
Claim 10 is rejected as vague for reciting, “further comprising preparing bilirubin from the compound represented by Formula 3”. According to claim 1, the compound represented by formula 3 can already be bilirubin (or, more appropriately mesobilirubin, see 35 USC § 112(a) Written Description Section) when R1, R2, and R4 are H and R3 is vinyl. So how can instant claim 10 further comprise preparing bilirubin, if it has already been prepared in claim 1? Appropriate clarification is required.
Claim 11 recites “The method according to claim 1, wherein the step of preparing a compound…”. This is insufficient antecedent basis for “a compound” as claim 1 recites multiple compounds. Appropriate correction is required.
Claim Rejections - 35 USC § 112(d)
The following is a quotation of 35 U.S.C. 112(d):
(d) REFERENCE IN DEPENDENT FORMS.—Subject to subsection (e), a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
The following is a quotation of pre-AIA 35 U.S.C. 112, fourth paragraph:
Subject to the following paragraph [i.e., the fifth paragraph of pre-AIA 35 U.S.C. 112], a claim in dependent form shall contain a reference to a claim previously set forth and then specify a further limitation of the subject matter claimed. A claim in dependent form shall be construed to incorporate by reference all the limitations of the claim to which it refers.
Claims 3-4 are rejected under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, as being of improper dependent form for failing to further limit the subject matter of the claim upon which it depends, or for failing to include all the limitations of the claim upon which it depends.
Claim 3 recites reacting the compound of Formula 1 with PEG, and then coupling with Formula 2. This would synthesize compound of both Formula 1 and 3, where R1 and R2 include PEG chains, which is a limitation in claim 3 that is broader than the claim—claim 1—from which it depends. Claim 1 recites the limitations of R1 and R2 as “each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 2 to 20 carbon atoms, an arylalkyl group having 7 to 20 carbon atoms, or a heteroarylalkyl group having 3 to 20 carbon atoms”. Importantly, the Specification does not provide a definition of alkyl, para 6-7, para [59], that embraces ether units, as required by a PEG unit. As such Claim 3 does not narrow, but in fact broadens, the claim from which it depends.
Claim 4 recites dimerizing a compound represented by Formula 6, where “X is an arylalkyl ester group having 8 to 20 carbon atoms, -CH2OH, -COOH, halogen atom or hydrogen.” However, the group corresponding to X in Formula 1 of claim 1 can only be an aldehyde. Thus, the X limitation in dependent claim 4 is not being further narrowed.
Applicant may cancel the claim(s), amend the claim(s) to place the claim(s) in proper dependent form, rewrite the claim(s) in independent form, or present a sufficient showing that the dependent claim(s) complies with the statutory requirements.
Claim Rejections - 35 USC § 112(a)
The following is a quotation of the first paragraph 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 the first paragraph of pre-AIA 35 U.S.C. 112:
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.
Written Description
Claims 1-15 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
Claim 1, and dependent claims 2-15, are directed towards a synthesis of bilirubin, comprising the following step:
[Formula 1] + [Formula 2] [Wingdings font/0xE0] [Formula 3]
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Such a coupling step can only lead to symmetrical compounds wherein the substituents on the outer 2-pyrrolidinone ring are in the same position with respect to the carbonyl group of the pyrrolidinone. In fact, such compounds are referred to in the literature as mesobilirubins. Brower 2001 displays the structural difference between bilirubin and mesobilirubins analogs quite succinctly (Figure 1, page 7870), shown below:
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Brower 2000 reports analogs in Figure 1, where R1 = n-butyl, R2 = methyl; R1 = methyl, R2 = n-butyl; R1 = ethyl, R2 = methyl; and R1 = methyl, R2 = ethyl. These substitution patterns create a plane of symmetry, and thus, mesobilirubin. This is the sort of substitution pattern embraced in the instant claims. However, bilirubin itself is not a symmetrical structure (see “Bilirubin” in Figure 1, above). Furthermore, the conversion of these symmetrical intermediates to the desired nonsymmetric bilirubin product is not further described or exemplified in the instant application. Meanwhile, Trull et al. (“A Generalized Method for Synthesizing Unsymmetric from Symmetric Bile Pigments”, published 1993)(hereinafter “Trull”) does report the conversion of mesobilirubin analogs to bilirubin analogs via an acid-catalyzed, constitutional isomerization scrambling reaction, using a DMSO/HCl protocol. This is not taught or shown in the instant application.
For the reasons taught above, Applicant did not possess a method of synthesizing bilirubin at the time of filing, and thus claims 1-15 are rejected.
Further, claims 2 and 3 are drawn to reacting the compound of Formula 3 and 1, respectively, with PEG. The Applicant has not shown possession of any compounds of Formula 3 or 1 with PEG units attached. As described in the Claim Interpretation section, PEG is understood to mean H-(O-CH2-CH2-)n-OH. However, the Specification only shows possession of reacting a compound of Formula 3 with methoxypolyethylene glycol amine, or mPEGn-NH2, instead.
For these reasons, Applicant did not possess a method of synthesizing bilirubin, further reacting the compounds of Formula 1 or Formula 3 with PEG, and thus, claims 2-3 are rejected.
Scope of Enablement
Claims 1-15 are rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for the following:
A method for synthesizing bilirubin, comprising preparing a compound represented by Formula 3 by coupling a compound represented by Formula 1 with a compound represented by Formula 2, (as recited in claim 1):
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where all the elements recited in claim 1 are enabled, except for R5, which is only enabled for hydrogen and not enabled tosyl or mesyl group.
does not reasonably provide enablement for elements that are outside the scope of the enabling elements listed above. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make the invention commensurate in scope with these claims.
To be enabling, the specification of the patent application must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557, 1561 (Fd. Cir. 1993). Explaining what is meant by "undue experimentation," the Federal Circuit has stated that:
The test is not merely quantitative, since a considerable amount of experimentation is permissible, if it is merely routine, or if the specification in question provides a reasonable amount of guidance with respect to the direction in which experimentation should proceed to enable the determination of how to practice a desired embodiment of the claimed invention. PPG v. Guardian, 75 F.3d 1558, 1564 (Fed. Cir. 1996). As pointed out by the court in In re Angstadt, 537 F.2d 498 at 504 (CCPA 1976), the key word is "undue", not "experimentation".
The factors that may be considered in determining whether a disclosure would require undue experimentation are set forth In re Wands, 8 USPQ2d 1400 (CAFC 1988) at 1404 wherein, citing Ex parte Forman, 230 USPQ 546 (Bd. Apls. 1986) at 547 the court recited eight factors:
1- the quantity of experimentation necessary,
2- the amount of direction or guidance provided,
3- the presence or absence of working examples,
4- the nature of the invention,
5- the state of the prior art,
6- the relative skill of those in the art,
7- the predictability of the art, and
8- the breadth of the claims
These factors are always applied against the background understanding that scope of enablement varies inversely with the degree of unpredictability involved. In re Fisher, 57 CCPA 1099, 1108, 427 F.2d 833, 839, 166 USPQ 18, 24 (1970). Keeping that in mind, the Wands factors are relevant to the instant fact situation for the following reasons:
The nature of the invention and state of the prior art:
The nature of the invention relates to a method for synthesizing bilirubin, comprising preparing a compound represented by Formula 3 by coupling a compound represented by Formula 1 with a compound represented by Formula 2, (as recited in claim 1). Claim 1 teaches that a compound of Formula 2 where R5 is tosyl or mesyl group, can be condensed with aldehyde of Formula 1 to prepare a compound of Formula 3. However, in the instant case, Applicant only demonstrates the preparation when R5 is hydrogen. The specification has no teaching or suggestion as to the viability for the reaction when R5 is mesyl or tosyl group, and there is no teaching in the prior art that suggests the condensation reaction can occur with a mesyl or tosyl group present.
Predictability of the art:
Hence, the process as applied to the above-mentioned compounds claimed above by the Applicant is not an art-recognized process and hence there should be adequate enabling disclosure in the specification with working example(s).
Level of skill in the art:
The specification has no support, as noted above, for preparing a compound of Formula 3 when R5 is a mesyl or tosyl group. The specification only demonstrates the preparation of a compound of Formula 3 when R5 is hydrogen.
The amount of direction provided, the presence or absence of working examples, and the quantity of experimentation necessary:
Example 26 “Preparation of Compound Ed” in Specification (page 48, para [380]-[383]) shows the process for the preparation of a compound of Formula 2, where the tosyl group is reduced to a hydrogen in the presence of NaBH4 to prepare compound Ed. Compound Ed is then coupled to prepare a compound of Formula 3 (Example 3.6 “Preparation of Compound D-Ed by coupling of Compound D and Compound Ed, page 61-62, para [489]-[493]).
Synthetic preparation methods for a compound of Formula 3 are not taught in the specification to provide for the aforementioned variables to include all of the possible substituents for R5 listed in claim 1. The quantity of experimentation needed would be an undue burden on skilled art in the chemical art since there is inadequate guidance given to the skilled artisan for the many reasons stated above.
Also, note MPEP 2164.08(b) which states that claims that read on "... significant numbers of inoperative embodiments would render claims nonenabled when the specification does not clearly identify the operative embodiments and undue experimentation is involved in determining those that are operative.". Clearly that is the case here. Thus, factors such as “sufficient working examples”, the “level of skill in the art and predictability, etc. have been demonstrated to be sufficiently lacking in the case for the instant claims. Genentech Inc. v. Novo Nordisk A/S (CA FC) 42 USPQ2d 1001, states that "a patent is not a hunting license. It is not a reward for search, but compensation for its successful conclusion" and "[p]atent protection is granted in return for an enabling disclosure of an invention, not for vague intimations of general ideas that may or may not be workable". MPEP §2164.01(a) states, “A conclusion of lack of enablement means that, based on the evidence regarding each of the above factors, the specification, at the time the application was ‘filed, would not have taught one skilled in the art how to make and/or use the full scope of the claimed invention without undue experimentation. In re Wright, 999 F.2d 1557,1562, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993).” That conclusion is clearly justified here and undue experimentation will be required to practice Applicants’ invention. Accordingly, the instant claims do not comply with the enablement requirement of 35 U.S.C. 112(a), since to practice the claimed invention a person of ordinary skill in the art would have to engage in undue experimentation, with no assurance of success.
Claims 2-15, which are dependent on claim 1, are also rejected for further requiring and/or reciting elements that are outside the scope of the enabling elements listed above.
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.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 1, 5, 12-15 are rejected under 35 U.S.C. 103 as being unpatentable over Brower 2000 in view of Chavan et al. (“Synthesis of 3-ethyl-4-methyl-1,5-dihydro-2H-pyrrol-2-one by Novel Palladium(II)-Catalyzed Cyclization and Ring-Closing Metathesis”, published 2015, cited in IDS filed on 12/10/2024)(hereinafter, “Chavan”).
Regarding claims 1 and 5: Brower 2000 teaches the synthetic preparation of a mesobilirubin analog (page 7870, Scheme 1; page 7881, “Des-2,18-ethyl-2,18-di-n-butyl-mesobilirubin-IIIα”) through the sequence, shown below:
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Brower 2000 teaches the same synthetic preparation as instant claim 1, where R1, R2, and R4 are H.
However, Brower 2000 does not teach a compound of Formula 2 where R3 is hydrogen, a vinyl group, an acetyl group, or an ethyl group substituted with a hydroxyl group, selenide, or sulifde.
Chavan teaches the synthesis of compounds 10a-g in Table, page 957. Reference compounds 13b and 13g read on compound of Formula 2 of instant claim 1, where R4 is a nitrogen protective group (PMB or Boc), R5 is H, and R3 is H.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2000 to use the compound disclosed by Chavan because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin.
Regarding claims 12-14: Brower 2000 teaches (page 7881, ”Des-2,18-ethyl-2,18-di-n-butyl-mesobilirubin-IIIα”) the reaction of instant claim 1 in methanol and water, heating at reflux (methanol boils at 65oC, water boils at 100oC), for 67 hours. Claim 12 recites a solvent selected from water and an alcohol, of which methanol is an alcohol; claim 13 recites a reaction temperature of -20 to 200oC; and claim 14 recites a reaction time of 0.5 to 120 hours. Therefore, they are rejected as obvious over Brower 2000 in view of Chavan. Furthermore….
Regarding claims 13 and 15: the claim language around temperatures and reagent amounts is language around temperature, concentrations, or reaction conditions, generally. Instant claim 13 recites a range of temperatures for the synthesis of compounds of Formula 3, and instant claim 15 recites range of ratios between the base and compound of Formula 1. In this instance, modifying concentrations or quantities and temperature (result effective variables) would be obvious based on routine optimization (In re Aller), unless there is evidence to the contrary. Furthermore, the specification does not show that modification of said variables is critical to the claimed invention. The selection of reaction conditions is more optimization by more modification of routine experimentation and within one skilled in the art. Change in temperature, concentration, or both is not patentable modification in the absence of unexpected results which is different in kind and not degree. Therefore, the determination of workable temperatures and concentrations would have been well within the practice of routine experimentation by the skilled artisan. Furthermore, absent any evidence demonstrating a patentable difference between the criticality of the temperature and base concentration, the determination of the optimum or workable temperature and base concentrations given the guidance of the prior art would have been generally prima facie obvious to the skilled artisan. It is well-established that merely selecting proportions and ranges is not patentable absent a showing of criticality. In re Becket, 33 U.S.P.Q. 33 (C.C.P.A. 1937). In re Russell, 439 F.2d 1228; 169 U.S.P.Q. 426 (C.C.P.A. 1971). Please see MPEP 2144.05 [R-2](II)(A) and In re Aller, 220 F. 2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). ("[W]here the general conditions of claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation."). Accordingly, claims 13 and 15 are rejected.
Claim 4 is rejected under 35 U.S.C. 103 as being unpatentable over Brower 2000 in view of Chavan et al. and Martin et al. (“Total Synthesis of Hematoporphyrin: A Conceptually New Approach”, published 2010, cited in IDS on 12/20/2024)(hereinafter, “Martin”).
Regarding claim 4: The teachings of Brower 2000 and Chavan were previously discussed, as applied to claim 1. Brower 2000 and Chavan do not teach the dimerization of a compound of Formula 6. The dimerization of a compound of Formula 6 in instant claim 4 is anticipated by Martin, who teaches (page 801, Scheme 3) the exact same synthetic preparation of the compound, shown below:
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Indeed, this is the same synthetic preparation used in the instant application (pages 23-25, para [202]-[216].
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2000 to use the compound disclosed by Chavan because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin. Furthermore, the disclosure of the method of claim 4 is directly taught by Martin.
Claims 6-7, and 10 are rejected under 35 U.S.C. 103 as being unpatentable over Brower 2000 in view of Olson et al. (“Hexahydro-1H-Isoindolinone-Like Scaffolds from Electronically Deactivated and Sterically Hindered Dienes: Synthesis in the Context of Muironolide A”, published 2015, cited in IDS on 12/20/2024)(hereinafter, “Olson”).
Regarding claims 6 and 7: The teachings of Brower 2000 were previously discussed, as applied to claim 1. Brower 2000 does not teach the cyclization of a compound of Formula 8. The cyclization of a compound of Formula 8 in instant claim 5, and the dehydration of the hydroxyl group of a compound of Formula 12 of instant claim 6, is anticipated by Olson, who teaches (page 2759, Scheme 13) the exact same synthetic preparation of the compounds, shown below:
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Indeed, this is the same synthetic preparation used in the instant application (pages 32-37, para [268]-[275]; [281-288]; and [294]-[303]. Reference compounds 40 and 46 read on compounds of Formula 11 and 12 (and product 29a thereof) of instant claim 5 and 6, respectively, where R4 is a nitrogen protective group.
Regarding claim 10: The preparation of 29a (above) taught by Olson reads on a compound of instant Formula 2 of instant claim 1. When combined with the prior art teachings, the compound of 29a is used to prepare a compound of instant Formula 3, that reads on the structure of bilirubin.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2000 to use the compound disclosed by Olson because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin. Furthermore, the disclosure of the methods of claims 6 and 7 are directly taught by Olson.
Claims 8 is rejected under 35 U.S.C. 103 as being unpatentable over Brower 2000 in view of Jacobi et al. (“New Syntheses of the C,D-Ring Pyrromethenones of Phytochrome and Phycocyanin”, published 2000, cited in IDS on 12/20/2024)(hereinafter, “Jacobi”).
Regarding claim 8: The teachings of Brower 2000 were previously discussed, as applied to claim 1. Brower 2000 does not teach the cyclization of a compound of Formula 13. The cyclization of a compound of Formula 13 in instant claim 8 is anticipated by Jacobi, who teaches (page 8480, Scheme 2) the exact same synthetic preparation of the compound, shown below:
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Indeed, this is the same synthetic preparation used in the instant application (pages 40-41, para [326]-[333]. Reference compound 15 reads on compounds of Formula 13 (and product thereof) of instant claim 5 and 6, respectively, where R4 is a nitrogen protective group and Y is selenide.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2000 to use the compound disclosed by Jacobi because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin. Furthermore, the disclosure of the method of claim 8 is directly taught by Jacobi.
Claims 9 is rejected under 35 U.S.C. 103 as being unpatentable over Brower 2000 in view of Kakiuchi et al. (“Total Synthesis of (±)-Phytochromobilin Starting from Two Pyrrole Derivatives”, published 1999, cited in IDS on 12/20/2024)(hereinafter, “Kakiuchi”).
Regarding claim 9: The teachings of Brower 2000 were previously discussed, as applied to claim 1. Kakiuchi does not teach the oxidation of a compound of Formula 14. The oxidation of a compound of Formula 14 in instant claim 9 is anticipated by Kakiuchi, who teaches (page 902, Scheme 3) the exact same synthetic preparation of the compound (19[Wingdings font/0xE0]20), shown below:
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Indeed, this is the same synthetic preparation used in the instant application (pages 45-46, para [364]-[367].
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2000 to use the compound disclosed by Kakiuchi because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin. Furthermore, the disclosure of the method of claim 9 is directly taught by Kakiuchi.
Claim 11 is rejected under 35 U.S.C. 103 as being unpatentable over Brower et al. (“Aromatic congeners of bilirubin: synthesis, stereochemistry, glucuronidation and hepatic transport”, published 2001, cited in IDS filed on 12/10/2024)(hereinafter, “Brower 2001”) in view of Chavan.
Regarding claim 11: Brower 2001 teaches the synthetic preparation of a mesobilirubin analogue (page 7815, Scheme 1; page 7825, “2,18-Des-vinyl-2,18-bis-phenyl-bilirubin-IIIα”) through the sequence, shown below, using piperidine base in the chemical transformation:
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Brower 2001 teaches the same synthetic preparation as instant claim 1, where R1, R2, and R4 are H.
However, Brower 2001 does not teach a compound of Formula 2 where R3 is hydrogen, a vinyl group, an acetyl group, or an ethyl group substituted with a hydroxyl group, selenide, or sulifde.
Chavan teaches the synthesis of compounds 10a-g in Table, page 957. Reference compounds 13b and 13g read on compound of Formula 2 of instant claim 1, where R4 is a nitrogen protective group (PMB or Boc), R5 is H, and R3 is H.
It would have been obvious to a person having ordinary skill in the art before the effective filing date of the claimed invention to modify the invention of Brower 2001 to use the compound disclosed by Chavan because it is no more than the simple substitution of one known element for another with the predictable result of synthesizing an analogue of mesobilirubin. Because Brower 2001 uses piperidine in this step, claim 11 is obvious over the prior art.
A reference is good not only for what it teaches by direct anticipation but also for what one of ordinary skill in the art might reasonably infer from the teachings. (In re Opprecht 12 USPQ 2d 1235, 1236 (Fed Cir. 1989); In re Bode 193 USPQ 12 (CCPA) 1976). In light of the forgoing discussion, the Examiner concludes that the subject matter defined by the instant claims would have been obvious within the meaning of 35 USC 103. From the teachings of the references, it is apparent that one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention as a whole is prima facie obvious to one of ordinary skill in the art at the time the invention was made, as evidenced by the references, especially in the absence of evidence to the contrary.
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 1-3 are provisionally rejected on the ground of nonstatutory double patenting as being unpatentable over at least claims 5-7 of copending Application No. 18/291,284 (reference application). Although the claims at issue are not identical, they are not patentably distinct from each other.
Regarding claims 5-7: Reference claim 5 is directed towards a method of synthesizing bilirubin by coupling a compound of Formula 4 with a mono-aldehyde compound of Formula 3 to form a compound of Formula 4, shown below, where R1 and R1’ are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 2 to 20 carbon atoms, an arylalkyl group having 7 to 20 carbon atoms, or a heteroarylalkyl group having 3 to 20 carbon atoms; R2 and R2’ are each hydrogen or a nitrogen protective group; and any one of X, X’, Y, and Y’ are a vinyl group, an acetyl group, a halogen atom, or an ethyl group substituted with a hydroxyl group, selenide, or sulifde, while the other is a methyl group.
[Formula 3] + [Formula 4] [Wingdings font/0xE0] [Formula 2]
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This is embraced by instant claim 1, directed towards a method of synthesizing bilirubin by coupling a compound of Formula 2 with a bis-aldehyde compound of Formula 1 to form a compound of Formula 3, shown below, where R1 and R2 are each independently hydrogen, an alkyl group having 1 to 12 carbon atoms, an aryl group having 6 to 20 carbon atoms, a heteroaryl group having 2 to 20 carbon atoms, an arylalkyl group having 7 to 20 carbon atoms, or a heteroarylalkyl group having 3 to 20 carbon atoms; R4 is each hydrogen or a nitrogen protective group; R5 is hydrogen; and any one of R3 is hydrogen, a vinyl group, an acetyl group, or an ethyl group substituted with a hydroxyl group, selenide, or sulifde.
[Formula 1] + [Formula 2] [Wingdings font/0xE0] [Formula 3]
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The reference and instant claims share at least one set of overlapping variables. The only difference is that the reference claim reacts the mono-aldehyde with the pyrrolidinone, while the instant claim reacts the bis-aldehyde with the pyrrolidinone. However, in the synthesis of instant Formula 3, the reaction mixture will inherently have a statistical mixture of bis-aldehyde starting material (instant Formula 1), mono-aldehyde starting material (reference Formula 3), and final product (reference Formula 2, instant Formula 3). Therefore, instant claim 1 reads on reference claim 5. Furthermore, instant claim 2 and 3, which depend on claim 1, are directed to the same limitations as reference claims 6 and 7, which depended on claim 5. Therefore, instant claims 2 and 3 read on reference claims 6 and 7, respectively.
This is a provisional nonstatutory double patenting rejection because the patentably indistinct claims have not in fact been patented.
Examiner Comments
Application 18/291,337 shares a lot of close similarities with the instant application. However, the major difference is that the compound of Formula 2 in reference claim 1 is slightly different than the compound of Formula 2 in instant claim 1, and so, the overall method is also different. The respective Markush structures do not overlap in any way, and thus, all dependent method claims are different claims. Furthermore, there are no obviousness-type claims. Therefore, a provisional NSDP rejection would not be appropriate.
CONCLUSION
All claims are rejected.
No claim is allowed.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to LUKE ALAN BORALSKY whose telephone number is (571)272-9746. The examiner can normally be reached Monday - Friday 7:30 am - 5:00 am.
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/L.A.B./Examiner, Art Unit 1624
/JEFFREY H MURRAY/Supervisory Patent Examiner, Art Unit 1624
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