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 .
Claim Status
Claims 1-8 are pending following the preliminary amendment filed 04/08/2024. Claims 1-8 are presently considered.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
The present application and all claims are being examined with the earliest effective filing date of 10/08/2021.
Information Disclosure Statement
The information disclosure statements (IDS) filed 04/08/2024, 09/17/2025 and 02/12/2026 have been considered by the examiner.
Claim Objections
Claim 1 is objected to because of the following informalities: for consistency, “N-acetylneuraminic acid and a N-acetylneuraminic acid-containing carbohydrate” recited in line 2 should be amended to recite “an N-acetylneuraminic acid and an N-acetylneuraminic acid-containing carbohydrate”. Appropriate correction is required.
Claim 2 is objected to because of the following informalities: square brackets should generally be avoided in patent claims, as they cause confusion with amendment markings. Please amend any recitation of a reference character presented in brackets, i.e., [1], [2] or [3], to recite the respective character in parentheses, i.e., (1), (2) or (3), in lines 2, 3, 6 and 9. Appropriate correction is required.
Claims 4 and 6-8 are objected to because of the following informalities: for consistency, “N-acetylneuraminic acid and a N-acetylneuraminic acid-containing carbohydrate” recited in lines 1-2 should be amended to recite “an N-acetylneuraminic acid and an N-acetylneuraminic acid-containing carbohydrate”. Appropriate correction is required.
Claim 4 is objected to because of the following informalities: for consistency, “at least one of N-acetylneuraminic acid” recited in line 5 should be amended to recite “at least one of the N-acetylneuraminic acid”. Appropriate correction is required.
Claims 6-8 are objected to because of the following informalities: for consistency, “least one of N-acetylneuraminic acid” recited in line 4 should be amended to recite “least one of the N-acetylneuraminic acid”. Appropriate correction is required.
Claim Interpretation
Claim 1 recites a microorganism “whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked”. This limitation is a product-by-process limitation, wherein the determination of patentability is based on the product itself, not its method of production. The specification does not provide any special redefinition of the term “blocked”. However, the specification does state that “[e]xamples of a method for blocking the ECA biosynthesis pathway include a method for causing loss of the activity of a protein associated with the ECA biosynthesis pathway” (see pg. 17, lines 10-14). The specification also discusses examples of methods for causing loss of the activity of a protein in this pathway, e.g., by knockout of a specific gene, inhibiting expression of a specific gene by RNAi, or introducing mutations into specific genes, etc. (see pg. 17, para. [0092]). However, the specification does not define “blocking” in such a manner as to limit the scope of the claim to any of these examples, and it should be noted that limitations from the specification are not read into the claims.
Therefore, the claim is given its broadest reasonable interpretation, wherein the microorganism has any absent or reduced activity associated with the ECA biosynthesis pathway. Note that this includes any absent or reduced activity of any element associated with this pathway, as well as any absent or altered structure associated with this pathway. Note also that the microorganism, as a product, must be evaluated based on its final structure, either as recited or as implied by the product-by-process steps (see MPEP 2113(I)). Therefore, any microorganism taught to be absent of any structure associated with the ECA biosynthesis pathway, including microorganisms that simply do not have an ECA pathway, are also within the scope of this limitation. This determination is further underlined by the fact that deleting multiple genes/enzymes in this pathway appear to be within the scope of the claims, including deleting every gene/enzyme in this pathway (e.g., removing the entire operon). Therefore, any microorganism that does not have this pathway must be considered to be within the scope of the limitation.
Applicant is advised that the recitation of “a protein consisting of an amino acid sequence represented by SEQ ID NO: X” is normally interpreted as encompassing a sequence of two or more amino acid residues contained within the recited SEQ ID NO, whereas the recitation of “a protein consisting of the amino acid sequence represented by SEQ ID NO: X” would be limited to the complete sequence of amino acid residues as specified by SEQ ID NO: X, and nothing more or less.
In the instant case, claim 2 recites “a protein consisting of an amino acid sequence represented by SEQ ID NO: [2, 4 or 6]” in lines 3, 6 and 9. The examiner notes that the specification does not provide any explicit definition of the term “protein” that would impose some lower limit on the size of what is encompassed by the term. Therefore, these limitations are given their broadest reasonable interpretation as encompassing any sequence of two or more amino acid residues contained within the recited SEQ ID NO.
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.
Claim 2 is 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.
Claim 2 recites “a homologous sequence thereof and having… [a recited] activity” in limitations 1-3, which renders the claim indefinite, because the term “homologous” is a relative term whose meaning is unclear within the context of the claim. While one could argue that “sequence homology” can be interpreted as “sequence identity”, there is no indication in the claim that “homology” is intended to mean “identity” and there is no requisite degree (e.g., percent identity) recited in the claim. One may also interpret a “homologous sequence” to be one that shares ancestry with the recited sequence, or perhaps serves the same function and/or has the same recited activity, while having some (or any) degree of structural similarity with the recited sequences. Furthermore, while some structures may be considered to be homologous, based on any of the factors above, others may be considered to be less homologous, and the specification does not provide a standard for ascertaining the requisite degree for any of these factors. Therefore, a person of ordinary skill would not be apprised as to which “homologous” structures would infringe upon the claim, and which would not. Accordingly, the metes and bounds have not been clearly set forth.
In the interest of compact prosecution, “a homologous sequence thereof” is reasonably interpreted as being any sequence in the art that is identified as having the recited activity. For example, any sequence disclosed in the art as having a “UDP-N-acetylglucosamine-undecaprenyl phosphate N-acetylglucosamine phosphotransferase (WecA) activity” would meet this limitation regardless of the degree of sequence similarity with SEQ ID NO: 2.
Claim Rejections - 35 USC § 112(a) – Written Description
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.
Claims 1-8 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 applications subject to pre-AIA 35 U.S.C. 112, the inventor(s), at the time the application was filed, had possession of the claimed invention.
Brief Statement of the Issue(s)
The claims are directed to any microorganism having an ability to produce N-acetylneuraminic acid or an N-acetylneuraminic acid-containing carbohydrate, wherein the microorganism’s enterobacterial common antigen (ECA) biosynthesis pathway is “blocked”, wherein the means for blocking said pathway is by any means, including the “lost” activity of a protein that is “homologous” to SEQ ID NOs 2, 4 or 6. In view of Applicant’s disclosure, the “blocking” of said pathway results in the improved production efficiency of NeuAc and/or NeuAc-containing carbohydrates (see specification at pg. 5, para. [0017]). However, the scope of the claims encompass any means to achieve the “blocking” of this pathway in any microorganism, including those possessing “homologous” sequences that do not clearly correspond to any particular set of prior art structures. In addition, the “blocking” of the ECA pathway is a product-by-process step, wherein any structure, or the lack thereof, in the claimed microorganism resulting in reduced activity of this pathway is encompassed by the claims.
Thus, in the absence of sufficient guidance or exemplification in the specification as filed, a person of skill could not have immediately envisaged from Applicant’s disclosure the full breadth of the claims, nor could they have reasonably concluded that the inventor(s) had possession of the full scope of the claimed invention.
Claim Scope
Claim 1 is representative of the pending claims scope and recites a microorganism whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked, encompassing any means to block this pathway in any microorganism having said pathway. It should be noted that the limitation, wherein the ECA biosynthesis pathway is “blocked”, is a product-by-process limitation, and is not necessarily directed to any particular structure. Therefore, any microorganism not having a fully functional ECA biosynthesis pathway, based on the presence or absence of any structure, is encompassed by the claim.
Furthermore, claim 2, which is within the scope of claim 1, recites the microorganism, wherein the activity of at least one protein is “lost”, said protein consisting of an amino acid sequence that is “homologous” to SEQ ID NOs 2, 4 or 6, and having WecA, WecB or WecC activity, respectively. While the claim recites the “loss” of activity associated with one of the recited structures, it is not specifically limited to any particular set of means to achieve this result. Furthermore, as discussed under 35 U.S.C. 112(b), the “homologous” sequences of the claim are directed to any sequence having the claimed activity. Note that the claim recites the loss of an activity, not the loss of any particular structure, and any structure (or lack thereof) associated with such loss of activity is within the scope of the claims.
In view of the specification, examples in which the function of a protein is lost, either reduced or completely stopped, includes: (i) all or a part of a DNA encoding the portion corresponding to the protein whose function is to be lost is removed; (ii) the substitution, deletion, or addition of one or several bases is performed on the DNA encoding the portion corresponding to the protein whose function is to be lost; or (iii) the DNA encoding the portion corresponding to the protein whose function is to be lost is substituted with a DNA sequence whose identity with a DNA sequence before modification is less than 80% (see pg. 16, para. [0087]; Emphasis added). It should also be noted that the specification states, “[t]he parent strain is any microorganism… preferably a prokaryote or a yeast strain” (see pg. 5, para. [0020]).
Note that the SEQ ID NOs recited in claim 2 have 367 to 420 amino acid residues. According to Reetz, M. (Laboratory evolution of stereoselective enzymes: a prolific source of catalysts for asymmetric reactions, Angew Chem Int Ed Engl, 2011 Jan 3;50(1):138-74; cited on Form 892), the random substitution of only three amino acid residues in an enzyme composed of 300 residues results in about 30 billion potential variants (see pg. 140, col. 1, para. 2 to col. 2, para. 1). Note that this broad genus of potential variants is not only relevant to the sequence modifications recited in the specification (i.e., “less than 80%”), but it is also relevant to the recited “homologous” sequences, which may have any sequence identity with the recited sequences, so long as they have the recited activity.
It should also be noted that the ECA biosynthesis pathway is present throughout the order of Enterobacterales (see Abstract of Rai, et al., Enterobacterial Common Antigen: Synthesis and Function of an Enigmatic Molecule, mBio, 2020 Aug 11;11(4):e01914-20; cited on Form 892). Hence, even if the claims were limited to only bacteria having an ECA pathway (which they are not), the microorganism of the claim would still encompass, at least, an entire order of bacteria.
Therefore, it is unclear if the claims encompass trillions of species or perhaps only a few in view of the functional limitations set forth in the claim(s). Accordingly, the claim scope reasonably appears to be vast and highly varied.
For clarity, the following paragraph broadly summarizes the issues affecting the breadth of each claim, which will be further explained in the following sections. Claims 1 and 4 are directed to any microorganism having the ECA pathway blocked by any means. Claims 2 and 6 are further directed to any microorganism having the ECA pathway blocked by the loss of an enzyme activity (as recited in claim 2) by any means (e.g., including any modification to a “homologous” sequence). Claims 3 and 7 are directed to an E. coli having the ECA pathway blocked by any means. Claims 5 and 8 are directed to an E. coli having the ECA pathway blocked by the loss of an enzyme activity (recited in claim 2) by any means (e.g., including any modification to a “homologous” sequence). Here, even the claims which recite the species of microorganism (i.e., Escherichia coli) are still at issue, because even when the protein associated with the activity is identified (e.g., E. coli WecA), the means for achieving the “lost” activity still encompasses a vast genus of potential modifications, which are discussed further below. For these reasons, claims 5 and 8, which have the narrowest scope, are included in this rejection.
Actual Reduction to Practice
In view of Applicant’s examples, three Escherichia coli BW25113 strains were engineered to have NeuAc activity by transforming into each strain a plasmid comprising NeuAc production genes (see pg. 26, para. [00139]; pg. 31, para. [0174]). A deletion of the yhbJ gene was also performed in each of the three strains (see pg. 27, para. [0144]), and the deletion of one of the genes, WecA, WecB or WecC, was performed in each of the three strains, respectively (see pg. 27, para. [0150]; pg. 29, para. [0158]; and pg. 30, para. [0166]). It is understood that WecA, WecB and WecC are each associated with ECA biosynthesis (see pgs. 17-18, paras. [0094], [0097] and para. [0099]). Therefore, three reductions to practice are disclosed, wherein the blocking of the ECA pathway was accomplished by the deletion of either WecA, WecB or WecC.
However, there is no reduction to practice that, for example, (1) was the result of disrupting the recited genes by any other means other than the complete deletion of the gene, (2) was the result of disrupting any other gene in the ECA pathway (e.g., WecD, WecE, WecF or WecG), (3) was the result of adding any additional elements to block expression, such as a repressor gene or RNAi, (4) or was accomplished using any microorganism other than Escherichia coli BW25113 ΔyhbJ.
According to the specification, yhbJ is a transcription factor that negatively regulates NeuAc biosynthesis (see pg. 16, lines 6-8). Therefore, it appears this deletion would be relevant to Applicant’s results of improved production efficiency of N-acetylneuraminic acid (NeuAc) (disclosed in Example 2). Therefore, it should be noted that this feature, while present in Applicant’s Examples, including those that achieved unexpected results, is not recited in any of the claims. It may be that Applicant does not deem this feature to have been critical to achieving the results of the invention, but there is also no evidence that these results would have been achieved without this feature.
Assessment of whether disclosed species are representative of the claimed genus
MPEP § 2163 states that a “representative number of species” means that the species which are adequately described are representative of the entire genus (see, e.g., MPEP § 2163(II)(3)(a), MPEP §2163.03(V)). Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus.
In this case, the claims encompass an essentially infinite number of microorganisms, but only one particular strain of E. coli was reduced to practice and further modified by the deletion of one of three closely-associated genes (WecA, WecB or WecC). Furthermore, there are zero reductions to practice using an E. coli strain that did not have the ΔyhbJ mutation. This is of particular relevance to even the narrowest claims (e.g., claims 5 and 8), because E. coli strains without this feature are still within their scope.
Although the MPEP does not define what constitutes a sufficient number of representative species, the Courts have indicated that the disclosure of two species within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618.
The Courts have also indicated that claims directed to a functionally defined genus of antibodies were not supported by a disclosure that "only describe[d] one type of structurally similar antibodies" that "are not representative of the full variety or scope of the genus." See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014).
Similarly, the disclosure of only one strain of bacterium having one type of mutation in one of three closely-associated genes in the ECA pathway, and zero embodiments using a strain not having the ΔybbJ mutation, does not provide sufficient disclosure to satisfy the written description requirement for the instantly claimed genus.
Identifying characteristics of the genus
In the absence of a reduction to practice of a representative number of species, the written description requirement for a claimed genus may be satisfied by disclosure of relevant, identifying characteristics, sufficient to show the applicant was in possession of the claimed genus.
The instant specification teaches that examples of the protein associated with the ECA biosynthesis pathway include WecA, WecB, WecC, WecD, WecE, WecF, and WecG (see pg. 17, para. [0093]). The specification also teaches that a method for obtaining a protein having a homologous sequence is “not particularly limited, and a well-known method can be used” (see pg. 20, para. [0112]). The specification teaches, as an example, that nucleotide sequences having an identity of preferably 80% to most preferably 99% or more with the nucleotide sequence encoding the target amino acid sequence are searched for in various gene sequence databases, and the homologous protein can be obtained by Southern hybridization against a chromosomal DNA library of the microorganism, preferably the genus Escherichia (see pg. 20, para. [0112]). The specification also states that the homologous sequence may be an amino acid sequence obtained by artificially deleting or substituting an amino acid residue from an original amino acid sequence or artificially inserting or adding an amino acid residue into the original amino acid sequence (see pg. 20, para. [0113]). The specification also discusses various examples of how an activity of a protein associated with the ECA pathway may be lost, as previously discussed under Claim Scope.
However, zero discussion is provided in the originally filed disclosure identifying what equivalent structures would be arrived at when seeking out such homologous proteins in microorganisms that are not Escherichia. Furthermore, there is zero disclosure as to which specific modifications (deletions, additions, substitutions) in the homologous proteins would have the intended effect, other than by deleting the gene associated with said protein. This lack of guidance is particularly relevant to the written description requirement, which is not equally conclusive to enablement. Even if one were to argue that the homologous sequences and their needed modifications can be easily discovered by a person of ordinary skill (e.g., by using a computer), the knowledge and level of skill in the art would not have permitted the ordinary artisan to immediately envisage the claimed genus of products that would arise from following this process.
Predictability in the Art
According to the prior art of Huszár, et al. (N-Acetylglucosamine-1-Phosphate Transferase, WecA, as a Validated Drug Target in Mycobacterium tuberculosis. Antimicrob Agents Chemother. 2017 Oct 24;61(11):e01310-17; cited on Form 892), the gene encoding the mycobacterial phosphoglycosyltransferase WecA in Mycobacterium tuberculosis was confirmed to be essential to the organism, and its transcriptional silencing was shown to be bactericidal in vitro and in macrophages (see Abstract). Huszár also discloses that a WecA homologue (MSMEG_4947) was previously confirmed to be essential in Mycobacterium smegmatis (see pg. 2, para. 1).
In view of Rai, et al. (previously cited), mutants defective in ECA biosynthesis trigger Rcs stress response activation in Serratia marcescens regardless of whether peptidoglycan biosynthesis is disrupted, suggesting that ECA may play an especially important role in envelope
integrity for this species. A role in envelope integrity is also suggested by the overproduction of outer membrane vesicles (OMV) in the absence of ECA in Serratia marcescens, suggesting an instability in the outer membrane. In contrast, a screen in E. coli K-12 revealed differences in OMV production in ECA biosynthesis mutants, but these phenotypes varied greatly depending on which gene was mutated, suggesting that the results may be indirect. It was also previously found that seven genes of the ECA operon are essential for serum resistance in E. coli; however, these effects may have been the result of the loss of O-antigen and/or isoprenoid carrier effects. See page 13, paragraph 2.
Rai also states that it is quite likely that the functions of ECA will be found to vary between the types of ECA and to occur on the level of cellular function as well as interaction with the environment (see pg. 14, para. 2).
Although the level of skill in the art is high, the predictability in the art is low due to the complexity of biological systems and the diversity of microorganisms and their enzymes. Specifically, an artisan would not be able to predict or identify, a priori, and in the absence of any guidance or consensus structures exactly which microorganisms would be capable of producing N-acetylneuraminic acid with increased productivity whose ECA biosynthesis pathway is “blocked”.
Accordingly, in the absence of sufficient structure/function teachings identifying particular genetic structures that are present throughout the claimed genus of microorganisms, that can be modified by any means to produce the same results exemplified by the present disclosure, which is required to practice the full scope of the claims, an artisan would not reasonably conclude that Applicant possessed the full scope of the broad and highly varied claim scope.
Conclusion
The description requirement of the patent statute requires a description of an invention, not an indication of a result that one might achieve if one made that invention. See In re Wilder, 736 F.2d 1516, 1521, 222 USPQ 369, 372-73 (Fed. Cir. 1984) (affirming rejection because the specification does "little more than outlin[e] goals appellants hope the claimed invention achieves and the problems the invention will hopefully ameliorate."). The courts have stated that “merely drawing a fence around a perceived genus is not a description of the genus. One needs to show that one has truly invented the genus, i.e., that one has conceived and described sufficient representative species encompassing the breadth of the genus. Otherwise, one has only a research plan, leaving it to others to explore the unknown contours of the claimed genus” (see, e.g., AbbVie v. Janssen, 111 USPQ2d 1780 (Fed. Cir. 2014) at 1789). In addition, the Courts have stated
“[r]egardless whether a compound is claimed per se or a method is claimed that entails the use of the compound, the inventor cannot lay claim to the subject matter unless he can provide a description of the compound sufficient to distinguish infringing compounds from non-infringing compounds, or infringing methods from non-infringing methods.” University of Rochester v. G.D. Searle Co., 69 USPQ2d 1886 1984 (CAFC 2004).
This is pertinent because, in the instant case, Applicants have claimed a broad and highly varied genus comprising an unknown number of species defined by reference to one or more functional limitations; however, the originally filed disclosure has failed to identify any common structure/function relationship sufficient to permit an artisan to identify what structures are included or excluded by the claim scope. This also means that the skilled artisan cannot envisage what structures infringe or do not infringe upon the pending claim scope.
In conclusion, for the reasons discussed above, the skilled artisan would not reasonably conclude that the inventor(s), at the time the application was filed, had possession of the full scope of the claimed invention.
Claim Rejections - 35 USC § 101
35 U.S.C. 101 reads as follows:
Whoever invents or discovers any new and useful process, machine, manufacture, or composition of matter, or any new and useful improvement thereof, may obtain a patent therefor, subject to the conditions and requirements of this title.
Claims 1-2 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a product of nature without significantly more. The rationale for this determination is explained below and is in keeping with the latest guidance regarding analysis of judicially excepted subject matter.
Subject Matter Eligibility Guidance
A three-step inquiry has been established to determine subject matter eligibility under 35 U.S.C. 101, in accordance with MPEP § 2106:
Step 1 – Is the claim directed to a process, machine, manufacture, or composition of matter?
Step 2A – Is the claim directed to a law of nature, natural phenomenon (product of nature), or an abstract idea?
Step 2A, prong 1 – Does the claim recite a law of nature, natural phenomenon, or an abstract idea?
Product of Nature Definition
When a law of nature or natural phenomenon is claimed as a physical product, the courts have often referred to the exception as a "product of nature". See Ass’n for Molecular Pathology v. Myriad Genetics, Inc., 569 U.S. 576, 580, 106 USPQ2d 1972, 1975 (2013); University of Utah Research Foundation v. Ambry Genetics, 774 F.3d 755, 758-59, 113 USPQ2d 1241, 1243 (Fed. Cir. 2014). As explained in those decisions, products of nature are considered to be an exception because they tie up the use of naturally occurring things, but they have been labeled as both laws of nature and natural phenomena. See Myriad Genetics, Inc., 569 U.S. at 590-91, 106 USPQ2d at 1979.
The Markedly Different Characteristics Analysis
The first step in the analysis is to select the appropriate counterpart to the nature-based product. When the nature-based product is derived from a naturally occurring thing, then the naturally occurring thing is the counterpart. See MPEP § 2106.04(c)(II)(A).
The second step in the analysis is to identify appropriate characteristics to compare. Appropriate characteristics must be possessed by the claimed product, because it is the claim that must define the invention to be patented. Cf. Roslin, 750 F.3d at 1338, 110 USPQ2d at 1673. See MPEP § 2106.04(c)(II)(B).
The final step in the markedly different characteristics analysis is to compare the characteristics of the claimed nature-based product to its naturally occurring counterpart in its natural state, in order to determine whether the characteristics of the claimed product are markedly different. See MPEP § 2106.04(c)(II)(C).
Step 2A, prong 2 – If the claim recites a judicial exception, does it recite additional elements that integrate the judicial exception into a practical application?
Limitations that are indicative of integration into a practical application include:
Improvements to the functioning of a computer, or to any other technology or technical field. See MPEP § 2106.05(a);
Applying the judicial exception with, or by use of, a particular machine. See MPEP § 2106.05(b);
Effecting a transformation or reduction of a particular article to a different state or thing. See MPEP § 2106.05(c);
Applying or using a judicial exception to effect a particular treatment or prophylaxis for a disease or medical condition. See MPEP § 2106.05(d);
Applying or using the judicial exception in some other meaningful way beyond generally linking the use of the judicial exception to a particular technological environment, such that the claim as a whole is more than a drafting effort designed to monopolize the exception. See MPEP § 2106.05(e).
Step 2B – If the recited judicial exception is not integrated into a practical application, does the claim recite additional elements that amount to significantly different than the judicial exception such that they provide an inventive concept? This step includes evaluation of the same considerations under Step 2A, Prong 2, as well as two additional considerations:
Adding a specific limitation or combination of limitations that are not well-understood, routine, conventional activity in the field, which is indicative that an inventive concept may be present; and
Simply appending well-understood, routine, conventional activities previously known to the industry, specified at a high level of generality, to the judicial exception, which is indicative that an inventive concept may not be present.
Analysis
Step 1: It must first be determined if the claim is to a statutory category and, if so, proceed to step 2A, prong 1. Claims 1-3 and 5 are directed to a microorganism and fall within the statutory category of a composition of matter.
Step 2A. prong 1: Prong 1 requires the Examiner to evaluate whether the claim recites a judicial exception and, if so, proceed to prong 2.
Independent claim 1 recites a microorganism which has an ability to produce at least one of an N-acetylneuraminic acid and an N-acetylneuraminic acid-containing carbohydrate and whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked.
Here, the recited limitation of “whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked” is a product-by-process step, wherein the patentability of the product does not depend on its method of production (see MPEP 2113(I)). Here, any microorganism that does not possess any one or more of the genes associated with this pathway is within the scope of the claim. This scope also includes microorganisms that do not possess an ECA pathway at all.
In view of the prior art of Linton et al. (Linton, et al. Multiple N-acetyl neuraminic acid synthetase (neuB) genes in Campylobacter jejuni: identification and characterization of the gene involved in sialylation of lipo-oligosaccharide. Mol Microbiol. 2000 Mar;35(5):1120-34; cited on Form 892), N-acetylneuraminic acid (NANA) is a common constituent of Camplyobacter jejuni lipo-oligosaccharide (LOS) (see pg. 1120, “Summary”). In view of the prior art of Rai, et al. (previously cited), the enterobacterial common antigen (ECA) biosynthesis pathway is common to the order Enterobacterales (see Abstract). In a search of the prior art, the examiner has not found any evidence that C. jejuni possesses this pathway at all. Hence, it is understood in view of the prior art of record, that naturally-occurring Camplyobacter jejuni is capable of producing an N-acetylneuraminic acid-containing carbohydrate, while this species does not possess an ECA biosynthesis pathway. Therefore, this microorganism, which is a naturally-occurring product, is within the scope of the claim.
If the nature-based product limitation is naturally occurring, there is no need to perform the markedly different characteristics analysis because the limitation is by definition directed to a naturally occurring product and thus falls under the product of nature exception. See MPEP 2106.04(c). Therefore, claim 1 recites the judicial exception.
Regarding claim 2, WecA, WecB and WecC are each associated with ECA biosynthesis (see instant specification at pgs. 17-18, paras. [0094], [0097] and para. [0099]). Hence, any microorganism not having these genes are within the scope of the claim for the same reasons discussed regarding claim 1. As naturally-occurring bacteria, such as C. jejuni, do not have these genes or the proteins they encode, claim 2 is still directed to the judicial exception.
Claims 3 and 5 recite the microorganism, which is Escherichia coli. It is understood that as a member of Enterobacterales, naturally occurring E. coli comprise a functioning ECA pathway (see, e.g., specification at pg. 2, para. [0009]). Moreover, E. coli must be artificially transformed by the introduction of NeuAc production genes in order to have the ability to produce NeuAc or NeuAc-containing carbohydrates, because naturally occurring E. coli do not have NeuAc synthase activity (see specification at pg. 11, para. [0048]). Therefore, the claimed microorganism is considered to have markedly different characteristics (e.g., NeuAc production genes and the ability to produce NeuAc) compared to its naturally occurring counterpart, which is the naturally occurring E. coli from which it was derived. Therefore, claims 3 and 5 are not directed to the judicial exception.
Step 2A, prong 2: Step 2A, prong 2 requires the Examiner to evaluate whether the claim recites additional elements that integrate the exception into a practical application of that exception and, if not, proceed to step 2B.
Claims 1 and 2 recite the microorganism without any additional elements other than the microorganism itself. Hence, there are no elements beyond the naturally occurring product to integrate the judicial exception into a practical application.
Step 2B: Step 2B requires the Examiner to first identify whether there are any additional elements (features/limitations/steps) recited in the claim beyond the judicial exception(s), and then evaluate those additional elements individually and in combination to determine whether they contribute to an inventive concept (i.e., amount to significantly more than the judicial exception(s)).
Claims 1 and 2 recite the microorganism without any additional elements other than the microorganism itself. Hence, there are no elements beyond the naturally occurring product that amount to significantly more than the judicial exception.
Therefore, claims 1-2 are not patent eligible.
Claim Rejections - 35 USC § 102
The following is a quotation of the appropriate paragraphs of 35 U.S.C. 102 that form the basis for the rejections under this section made in this Office action:
A person shall be entitled to a patent unless –
(a)(1) the claimed invention was patented, described in a printed publication, or in public use, on sale, or otherwise available to the public before the effective filing date of the claimed invention.
(a)(2) the claimed invention was described in a patent issued under section 151, or in an application for patent published or deemed published under section 122(b), in which the patent or application, as the case may be, names another inventor and was effectively filed before the effective filing date of the claimed invention.
Claim(s) 1-8 is/are rejected under 35 U.S.C. 102(a)(2) as being anticipated by Aesaert et al., US 2022/0396817 A1, effectively filed 02/14/2020 (cited on Form 892), hereafter, “Aesaert”.
Regarding claim 1, Aesaert teaches a microorganism genetically modified for production of at least one glycosylated product, wherein the microorganism has a reduced cell wall biosynthesis by a reduced common-antigen biosynthesis (see claim 47), wherein the glycosylated product is an oligosaccharide (see claim 49), wherein the reduction in the common-antigen biosynthesis is provided by reduced expression of at least one of the genes present in the common-antigen biosynthesis gene cluster, including UDP-N-acetylglucosamine-undecaprenyl-phosphate N-acetylglucosamine phosphotransferase, UDP-N-acetylglucosamine 2-epimerase, and UDP-N-acetyl-D-mannosamine dehydrogenase (see claim 57).
In view of the instant specification, the genes of the common-antigen biosynthesis gene cluster above are the same as the genes whose expression is associated with the enterobacterial common antigen (ECA) biosynthesis pathway (see instant specification at pgs. 17-18, paras. [0094], [0097] and para. [0099]) and are also recited in dependent claim 2.
Aesaert teaches that the term “glycosylated product” refers to molecules comprising at least one monosaccharide (see pg. 3, para. [0026]) including N-acetylneuraminic acid (see pg. 4, para. [0027]). Aesaert teaches that the oligosaccharide may be a “sialylated oligosaccharide” (see pg. 5, para. [0035]), which is defined as a sugar polymer containing at least two monosaccharide units, at least one of which is a sialyl (N-acetylneuraminyl) moiety (see pg. 5, para. [0038]). Aesaert teaches that the sialylated oligosaccharide may be one bearing one or several “sialic acid” residues (see pg. 6, para. [0039]), and that the term “sialic acid” refers to N-acetylneuraminic acid (see pg. 6, para. [0045]). Hence, Aesaert teaches the microorganism is engineered to produce glycosylated products, including N-acetylneuraminic acid and N-acetylneuraminic acid-containing carbohydrates.
Therefore, Aesaert teaches a microorganism which has an ability to produce at least one of an N-acetylneuraminic acid and an N-acetylneuraminic acid-containing carbohydrate and whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked.
Regarding claim 2, Aesaert teaches the microorganism, wherein the reduction in the common-antigen biosynthesis is provided by reduced or abolished expression of at least one of the genes present in the common-antigen biosynthesis gene cluster, including UDP-N-acetyl-D-mannosamine dehydrogenase (see claim 57). Aesaert further teaches the microorganism, wherein the reduction in the common-antigen biosynthesis is provided by reduced expression of a polypeptide sequence comprising SEQ ID NO: 18 and having UDP-N-acetyl-D-mannosamine dehydrogenase activity (see claim 58). As shown in the following alignment, instant SEQ ID NO: 6 (top) is identical to Aesaert’s SEQ ID NO: 18 (bottom):
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102
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102
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Hence, Aesaert teaches the microorganism, wherein an activity of (3) a protein, consisting of an amino acid sequence represented by SEQ ID NO: 6 and having UDP-N-acetylmannosamine dehydrogenase (WecC) activity, is lost.
Regarding claim 3, Aesaert teaches the microorganism is a bacterium of Escherichia (see claim 52).
Aesaert discloses that “[t]he term ‘micro-organism’ or ‘cell’ as used herein refers to a microorganism chosen from the list consisting of a bacterium… preferably belongs to the phylum of the Protobacteria… preferably to the family Enterobacteriaceae… preferably to the species Escherichia coli” (see pg. 10, para. [0078]). Aesaert also states that “[t]he disclosure specifically relates to a mutated and/or transformed Escherichia coli as indicated above wherein the E. coli strain is a K12 strain” (see pg. 10, para. [0079]). Furthermore, Aesaert’s SEQ ID NO: 18 is identified as “Escherichia coli” (see pg. 48, “Organism”). It should also be noted that E. coli is the only species of Escherichia that is recited in Aesaert’s disclosure, including Aesaert’s working examples. Therefore, it would have been apparent to an ordinary artisan that “Escherichia coli” is the only species of “Escherichia” that is expressly taught by Aesaert for use as the microorganism.
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)). In the instant case, the embodiment of Aesaert’s claim 52 (which depends from independent claim 47) is expressly Escherichia, and it is clear in view of the disclosure as a whole that Escherichia coli is the only species of this genus that is expressly considered by Aesaert for any of the compositions and methods disclosed by the reference.
Regarding claim 4, Aesaert teaches a method for producing a glycosylated product by a genetically modified cell, comprising the steps of: providing a cell genetically modified for the
production of a glycosylated product, the cell comprising at least one nucleic acid sequence coding for an enzyme for glycosylated product synthesis, the cell further genetically modified for reduced cell wall biosynthesis, by reduced expression of at least one enzyme within the cell
wall biosynthesis pathway, wherein the cell wall biosynthesis pathway is the cell wall carbohydrate antigen biosynthesis pathway, preferably wherein the cell wall carbohydrate antigen biosynthesis is common-antigen biosynthesis; and culturing the cell in a medium under conditions permissive for the production of the glycosylated product (see pg. 13, paras. [0110]-[0114]), wherein the genetically modified cell is any microorganism as described herein, preferably Escherichia (see pg. 13, para. [0115]).
Aesaert states that the “term ‘glycosylated product’ as used herein refers to the group of molecules comprising at least one monosaccharide as defined herein”, including oligosaccharides (see pg. 3, para. [0026]), and the “term ‘monosaccharide’ as used herein refers to saccharides containing only one simple sugar” including “N-acetylneuraminic acid” (see pgs. 3-4, para. [0027]; Emphasis added). Furthermore, Aesaert states that “the glycosylated product produced by the methods disclosed herein can be any glycosylated product described herein” (see pg. 15, para. [0135]; Emphasis added).
Aesaert teaches that the genes present in the common-antigen biosynthesis gene cluster include UDP-N-acetylglucosamine-undecaprenyl-phosphate N-acetylglucosamine phosphotransferase, UDP-N-acetylglucosamine 2-epimerase, and UDP-N-acetyl-D-mannosamine dehydrogenase (see pg. 11, para. [0096]) which are the same as the genes whose expression is associated with the enterobacterial common antigen (ECA) biosynthesis pathway, as previously discussed.
Therefore, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing a microorganism, which has an ability to produce N-acetylneuraminic acid and whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked, in a culture medium to produce N-acetylneuraminic acid.
Regarding claim 5, Aesaert teaches the microorganism is a bacterium of Escherichia (see claim 52).
Aesaert discloses that the “term micro-organism’ or ‘cell’ as used herein refers to a microorganism chosen from the list consisting of a bacterium… preferably belongs to the phylum of the Protobacteria… preferably to the family Enterobacteriaceae… preferably to the species Escherichia coli” (see pg. 10, para. [0078]). Aesaert also states that “[t]he disclosure specifically relates to a mutated and/or transformed Escherichia coli as indicated above wherein the E. coli strain is a K12 strain” (see pg. 10, para. [0078]). Furthermore, Aesaert’s SEQ ID NO: 18 is identified as “Escherichia coli” (see pg. 48, “Organism”). It should also be noted that E. coli is the only species of Escherichia that is recited in Aesaert’s disclosure. Therefore, it would have been apparent to an ordinary artisan that “Escherichia coli” is the only species of “Escherichia” that is expressly taught by Aesaert for use as the microorganism.
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)). In the instant case, the embodiment of Aesaert’s claim 52 (which depends from independent claim 47) is expressly Escherichia, and it is clear in view of the disclosure as a whole that Escherichia coli is the only species of this genus that is expressly considered by Aesaert for any of the compositions and methods disclosed by the reference.
Regarding claim 6, Aesaert teaches a method for producing a glycosylated product by a genetically modified cell, comprising the steps of: providing a cell genetically modified for the
production of a glycosylated product, the cell comprising at least one nucleic acid sequence coding for an enzyme for glycosylated product synthesis, the cell further genetically modified for reduced cell wall biosynthesis, by reduced expression of at least one enzyme within the cell
wall biosynthesis pathway, wherein the cell wall biosynthesis pathway is the cell wall carbohydrate antigen biosynthesis pathway, preferably wherein the cell wall carbohydrate antigen biosynthesis is common-antigen biosynthesis; and culturing the cell in a medium under conditions permissive for the production of the glycosylated product (see pg. 13, paras. [0110]-[0114]), wherein the genetically modified cell is any microorganism as described herein, preferably Escherichia (see pg. 13, para. [0115]).
Aesaert states that the “term ‘glycosylated product’ as used herein refers to the group of molecules comprising at least one monosaccharide as defined herein”, including oligosaccharides (see pg. 3, para. [0026]), and the “term ‘monosaccharide’ as used herein refers to saccharides containing only one simple sugar” including “N-acetylneuraminic acid” (see pgs. 3-4, para. [0027]; Emphasis added). Furthermore, Aesaert states that “the glycosylated product produced by the methods disclosed herein can be any glycosylated product described herein” (see pg. 15, para. [0135]; Emphasis added).
Aesaert teaches that the genes present in the common-antigen biosynthesis gene cluster include UDP-N-acetylglucosamine-undecaprenyl-phosphate N-acetylglucosamine phosphotransferase, UDP-N-acetylglucosamine 2-epimerase, and UDP-N-acetyl-D-mannosamine dehydrogenase (see pg. 11, para. [0096]) which are the same as the genes whose expression is associated with the enterobacterial common antigen (ECA) biosynthesis pathway, as previously discussed. Aesaert teaches that UDP-N-acetyl-D-mannosamine dehydrogenase (wecC) is represented by SEQ ID NO: 18 (see pg. 11, para. [0096]), which is identical to instant SEQ ID NO: 6, as previously discussed.
Therefore, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing a microorganism, wherein an activity of a protein having UDP-N-acetylmannosamine dehydrogenase (WecC) activity is lost, in a culture medium to produce N-acetylneuraminic acid.
Regarding claim 7, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing a microorganism, which has an ability to produce N-acetylneuraminic acid and whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked, in a culture medium to produce N-acetylneuraminic acid, as discussed regarding claim 4. Aesaert further teaches the same method (see pg. 13, paras. [0110]-[0114]), wherein the genetically modified cell is “any microorganism as described herein, preferably Escherichia” (see pg. 13, para. [0115]; Emphasis added).
Aesaert discloses that “[t]he term ‘micro-organism’ or ‘cell’ as used herein refers to a microorganism chosen from the list consisting of a bacterium… preferably belongs to the phylum of the Protobacteria… preferably to the family Enterobacteriaceae… preferably to the species Escherichia coli” (see pg. 10, para. [0078]). Aesaert also states that “[t]he disclosure specifically relates to a mutated and/or transformed Escherichia coli as indicated above wherein the E. coli strain is a K12 strain” (see pg. 10, para. [0079]). Furthermore, Aesaert’s SEQ ID NO: 18 is identified as “Escherichia coli” (see pg. 48, “Organism”). It should also be noted that E. coli is the only species of Escherichia that is recited in Aesaert’s disclosure. Therefore, it would have been apparent to an ordinary artisan that “Escherichia coli” is the only species of “Escherichia” that is expressly taught by Aesaert for the methods of the disclosure.
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)). In the instant case, the microorganism of Aesaert’s method is expressly Escherichia, and it is clear in view of the disclosure as a whole that Escherichia coli is the only species of this genus that is expressly considered by Aesaert for any of the compositions and methods disclosed by the reference.
Therefore, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing an Escherichia coli strain, which has an ability to produce N-acetylneuraminic acid and whose enterobacterial common antigen (ECA) biosynthesis pathway is blocked, in a culture medium to produce N-acetylneuraminic acid.
Regarding claim 8, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing a microorganism, wherein an activity of a protein having UDP-N-acetylmannosamine dehydrogenase (WecC) activity is lost, in a culture medium to produce N-acetylneuraminic acid, as discussed regarding instant claim 6. Aesaert further teaches the same method (see pg. 13, paras. [0110]-[0114]), wherein the genetically modified cell is “any microorganism as described herein, preferably Escherichia” (see pg. 13, para. [0115]; Emphasis added).
Aesaert discloses that the “term micro-organism’ or ‘cell’ as used herein refers to a microorganism chosen from the list consisting of a bacterium… preferably belongs to the phylum of the Protobacteria… preferably to the family Enterobacteriaceae… preferably to the species Escherichia coli” (see pg. 10, para. [0078]). Aesaert also states that “[t]he disclosure specifically relates to a mutated and/or transformed Escherichia coli as indicated above wherein the E. coli strain is a K12 strain” (see pg. 10, para. [0079]). Furthermore, Aesaert’s SEQ ID NO: 18 is identified as “Escherichia coli” (see pg. 48, “Organism”). It should also be noted that E. coli is the only species of Escherichia that is recited in Aesaert’s disclosure. Therefore, it would have been apparent to an ordinary artisan that “Escherichia coli” is the only species of “Escherichia” that is expressly taught by Aesaert for the methods of the disclosure.
A reference disclosure can anticipate a claim when the reference describes the limitations but "'d[oes] not expressly spell out' the limitations as arranged or combined as in the claim, if a person of skill in the art, reading the reference, would ‘at once envisage’ the claimed arrangement or combination." Kennametal, Inc. v. Ingersoll Cutting Tool Co., 780 F.3d 1376, 1381, 114 USPQ2d 1250, 1254 (Fed. Cir. 2015) (quoting In re Petering, 301 F.2d 676, 681(CCPA 1962)). In the instant case, the microorganism of Aesaert’s method is expressly Escherichia, and it is clear in view of the disclosure as a whole that Escherichia coli is the only species of this genus that is expressly considered by Aesaert for any of the compositions and methods disclosed by the reference.
Therefore, Aesaert teaches a method for producing N-acetylneuraminic acid, the method comprising culturing an Escherichia coli strain, wherein an activity of a protein having UDP-N-acetylmannosamine dehydrogenase (WecC) activity is lost, in a culture medium to produce N-acetylneuraminic acid.
Conclusion
No claims are allowed.
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/DENNIS IGNATIUS ARMATO JR/Examiner, Art Unit 1651
/MELENIE L GORDON/Supervisory Patent Examiner, Art Unit 1651
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