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 .
The response and amendment filed 3-19-2026 has been entered into the record.
Status of Claims
Claims 1-7, 12, 17, 18 and 21 are pending.
Sequence Requirements
This application contains sequence disclosures that are encompassed by the definitions for nucleotide and/or amino acid sequences set forth in 37 C.F.R. § 1.821(a)(1) and (a)(2). However, this application fails to comply with the requirements of 37 C.F.R. § § 1.821-1.825 for the reason(s) set forth below.
The reference to the sequence listing is improper as it must list the size in bytes not KB as current. (see preliminary amendment filed 6-9-2023).
Figure 10 has sequences that are not followed by a unique sequence identifier either in the Figure or in the Description of Figure 10.
Page 37 recites multiple sequences that are not each followed by a proper sequence identifier.
Full compliance with the sequence rules is required in response to this office action.
Priority
Receipt is acknowledged of certified copies of papers required by 37 CFR 1.55.
Election/Restrictions
Applicant’s election of Group I and species of a modified rspA gene, a modified rspA operon and/or a modified 30S ribosomal protein S1) without traverse is acknowledged. Claims 1-7, 12, 17, 18 and 21 are under examination.
Information Disclosure Statement
The information disclosure statement has been considered. An initialed copy is enclosed.
Claim Objections
Applicant is advised that should claim 1 be found allowable, claim 21 will be objected to under 37 CFR 1.75 as being a substantial duplicate thereof. When two claims in an application are duplicates or else are so close in content that they both cover the same thing, despite a slight difference in wording, it is proper after allowing one claim to object to the other as being a substantial duplicate of the allowed claim. See MPEP § 608.01(m).
Claim Rejections - 35 USC § 112
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 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(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.
Claims 1-7, 12, 17, 18 and 21 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. This is a written description rejection.
The factors considered in the Written Description requirement are (1) level of skill and knowledge in the art, (2) partial structure, (3) physical and/or chemical properties, (4) functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the (5) method of making the claimed invention. While all of the factors have been considered, only those required for a prima facie case are set forth below.
The claims recite a modified Gram-negative cell comprising a modified rspA gene, a modified rspA operon and/or a modified 30S ribosomal protein S1 providing for mutations without limitation (see all the claims) including claims 4-7 having phenotypic properties of increased nOMV production and culture characteristics. In consideration of a partial structure/correlation between structure and function along with disclosed physical and chemical properties, the following is found.
The specification teaches 3 transposon (Tn5) insertional mutations in B. pertussis rspA gene set forth in Figure 3 and occurred downstream of the R3 domain of the gene and at page 31 lines 18-24 and resulted in deletion of downstream sequences and production of a truncated ribosomal S1 proteins.
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The C-terminal truncations were confirmed in other Gram-negative bacteria to correlate with the hyper-blebbing phenotype as compared to the parental wild-type strain of Gram-negative bacterium under the identical culture conditions. (see page 42, lines 33-36). Other than the specific C-terminal truncations and mutations provided in Figure 3, specific sequence changes to the ribosomal protein encoded by rspA have not been disclosed nor correlated with the claimed phenotypes of hyper-blebbing and the culturing characteristics set forth in claim 5.
No mutations to the rspA operon have been similarly disclosed that provide for increased nOMV production. In fact, the rspA operon is not described for the vast majority of the Gram-negative bacteria and is not described herein the correlation of structure or partial structure with phenotypic blebbing is undisclosed. There are no disclosed mutations in these unknown areas of unknown rspA operons that have been demonstrated correlate with nOMV hyper-blebbing in a representative number of Gram-negative organisms. There is no correlation with these claimed operon mutations with nOMV hyper-blebbing. No mutation in the rspA gene/operon/or rspA protein has been described that has more than 10-fold increase by any measure set forth in the specification. The specification lacks description of a representative number of mutations in the rspA operon of Gram-negative bacteria and provides no correlation thereof with the phenotypes set forth in the claims. The specification fails to teach point mutations or insertions or general deletions in the 30S ribosomal S1 protein, other than the C-terminal specifically disclosed truncations by Tn5 mutation provide for some, but not all of the phenotypic properties claimed. Some mutations in the rspA gene encoding ribosomal protein were well known in the art to be lethal and it is therefore uncertain where other mutations and the type of mutations that can be developed in the gene and protein that provide for the phenotypic properties set forth in the claims. It is well established that the rates of outer membrane vesicle production are not uniform, even for a particular strain as production has long been seen to be influenced by environmental factors and sources of cellular stress (Ellis et al (Microbiology and Molecular Biology Reviews, 74(1):81-94, 2010; of record) see page 83, column 2, first paragraph. In the absence of a comparison to the specific wild-type parental strain and culture conditions defined, the basis for increased nOMV production cannot be ascertained.
The claims are not limited to C-terminal truncations of the rspA gene in B. pertussis or corresponding regions in other Gram-negative bacteria, but random insertion or point mutation changes and/or random deletions across the entire gene or operon or limited to specific positions having different structure (see claims 4-7, 12 and 21). The specification does not teach the structure of the rspA operon in Gram-negative bacteria, nor does it describe point mutations in the protein, insertions or deletions in the protein or in the gene as is broadly claimed. As such, it is found that the specification does not set forth a reasonable correlation of the recited structures with the scope of the claimed structural changes with the phenotypic properties as claimed. Vas-Cath Inc. v. Mahurkar, 19 USPQ2d 1111, makes clear that "applicant must convey with reasonable clarity to those skilled in the art that, as of the filing date sought, he or she was in possession of the invention. The invention is, for purposes of the 'written description' inquiry, whatever is now claimed." (See page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is claimed." (See Vas-Cath at page 1116.)
Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential method for isolating it. The nucleic acid itself is required. See Fiers v. Revel, 25 USPQ2d 1601, 1606 (CAFC 1993) and Amgen Inc. V. Chugai Pharmaceutical Co. Ltd., 18 USPQ2d 1016. In Fiddes v. Baird, 30 USPQ2d 1481, 1483, claims directed to mammalian FGF's were found unpatentable due to lack of written description for the broad class. The specification provided only the bovine sequence. Finally, University of California v. Eli Lilly and Co., 43 USPQ2d 1398, 1404, 1405 held that: ...To fulfill the written description requirement, a patent specification must describe an invention and do so in sufficient detail that one skilled in the art can clearly conclude that "the inventor invented the claimed invention." Lockwood v. American Airlines, Inc. , 107 F.3d 1565, 1572, 41 USPQ2d 1961, 1966 (1997); In re Gosteli , 872 F.2d 1008, 1012, 10 USPQ2d 1614, 1618 (Fed. Cir. 1989) (" [T]he description must clearly allow persons of ordinary skill in the art to recognize that [the inventor] invented what is claimed."). Thus, an applicant complies with the written description requirement "by describing the invention, with all its claimed limitations, not that which makes it obvious," and by using "such descriptive means as words, structures, figures, diagrams, formulas, etc., that set forth the claimed invention." Lockwood , 107 F.3d at 1572, 41 USPQ2d at 1966.
The species specifically disclosed are not representative of the genus because the genus is highly variant covering an incalculable number of bacteria as all Gram-negative bacteria have not been discovered/identified. The claimed mutations are vast and unlimited. Weighing all the factors, the breadth of the claims, the lack of correlation between structure and function of the claimed scope of mutations, level of knowledge and skill in the art, one of ordinary skill in the art would not recognize from the disclosure that the applicant was in possession of the full genus of modified rspA gene, modified rspA operon or modified 30S ribosomal protein as claimed which would successfully provide for the phenotypic properties of increased nOMV production and the culture characteristics as claimed. At best, it simply indicates that one should run tests on a wide spectrum of rspA gene/operon/protein mutations in different Gram-negative bacteria in the hope that at least one of them will work. Therefore, the written description requirement is prima facie not satisfied. Applicant is reminded that Vas-Cath makes clear that the written description provision of 35 USC 112 is severable from its enablement provision. (See page 1115.)
Claims 2-7 are rejected under 35 U.S.C. 112(b), as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor, or for pre-AIA the applicant regards as the invention.
As to claims 2-7, the claims are indefinite in the use of “capable of” because it is unclear if the functional property is required. Additionally, the comparison is unclear because it does not distinguish between different unmodified parent strain and any other unmodified bacterial cell. As such, the basis for comparison is unclear.
As to claims 3-7, the claims are unclear in the recitation of the and/or between the different embodiments as some of the embodiments are mutually exclusive.
As to claim 5 embodiment (iv), the claim makes no sense as the claim recites “no later than 120 hours” and then recites 1, 2, 3, etc. It appears that some language is missing. Clarification is requested.
As to claim 6, embodiments c, d, k and l, it is unclear what the percent identity language refers to as the list specifically provides for “a designated nucleotide sequence comprising:”. It is unclear how the percent identity language defines the designated nucleotide sequence position where the mutation occurs. Clarification is requested.
As to claims 6 and 7, the claims reference domains R3 and R4, however these domains to not appear in all Gram-negative bacteria in the recited 30S ribosomal protein S1 and are only set forth in the specification in relation to B. pertussis as such the generic reference is unclear as it relates to the vast genus.
Claim 21 is rejected under 35 U.S.C. 112(d), 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. The claim fails to further limit the gram-negative bacterial cell of claim 1. 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 § 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 17 and 18 are rejected under 35 U.S.C. 101 because the claimed invention is directed to non-statutory subject matter. The claim(s) does/do not fall within at least one of the four categories of patent eligible subject matter because the claims are drawn to natural products.
Claims 17 is drawn to native outer membrane vesicles (nOMV) per se interpreted as a product by process and claims 18 is drawn to a vaccine composition comprising nOMVs. Ellis et al (Microbiology and Molecular Biology Reviews, 74(1):81-94, 2010; of record) teaches that all Gram-negative bacteria investigated to date naturally release outer membrane vesicles. Calculations of native outer membrane vesicle production show that the vesicles represent a significant fraction of cellular material (see page 83, column 1, first paragraph).
Because the claimed nOMVs are composed of matter, at least one embodiment encompassed within the broadest reasonable interpretation (BRI) of instant claims is directed to a statutory category, i.e., a composition of matter (Step 1: YES). The as filed specification does not provide a structural distinction between the nOMVs produced from the parent/wild-type strain and the mutant strain of claim 1. As such, the “obtained or obtainable” from does not provide a distinction from the naturally occurring nOMVs that the art of Ellis et al acknowledges are produced by Gram-negative bacteria.
Therefore, the claimed nOMVs do not differ from naturally occurring nOMVs produced by the unmodified bacteria species. There is no evidence that the claimed nOMVs are modified in any way and are markedly different from what exist in nature. Supreme Court has made it clear in Myriad that eligibility requires the creation of something not naturally occurring, which is markedly different from what exists in nature. Unlike the Chakrabarty bacterium, which was new “with markedly different characteristics from any found in nature” Diamond v. Chakrabarty, 447 U.S. 303 (1980) at 310, 100 S. Ct. 2204, 65 L. Ed. 2d 144, due to the multiple additional plasmids and resultant “capacity for degrading oil”, there is no indication that the instantly claimed strain(s) are genetically manipulated or structurally modified in any marked or significant way such that the structural difference results in change of properties of the strain(s). Furthermore, the ability to generate nOMVs represent the inherent qualities, properties or characteristics inseparable from said naturally occurring strain(s) and therefore are a handiwork of nature. In Chakrabarty and Myriad, the marked difference inquiry was focused on the modified structural characteristics of the product, not how it was used or how it was made. Note that “….. patents cannot issue for the discovery of phenomena of nature”. Le Roy v. Tatham, 14 How. 156, 175 (1853). The qualities of the bacteria, like the heat of the sun, electricity, or the qualities of metals, are part of the storehouse of knowledge of all men. They are manifestations of laws of nature, free to all men and reserved exclusively to none.” See Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. at 130, 1948. In Funk Brothers, the Court held that the composition was not patent eligible because the patent holder did not alter the bacteria in any way. Since each component of the instantly claimed products are a ‘product of nature’ exception, and the claims are directed to a judicial exception (Step 2A Prong One: YES). Judicial exceptions include all natural products including those derived from natural sources or patients such as naturally occurring microorganisms, proteins, peptides, glycoproteins, glycopeptides, carbohydrates, and other substances found in or derived therefrom, or from nature. Next, the claims as a whole are analyzed to determine whether any additional element, or combination of elements, is sufficient to ensure that the claims amount to significantly more than the exceptions. Having the two naturally occurring (e.g. nOMVs) in a vaccine composition does not amount to significantly more. There is nothing that provides significantly more or that integrates the claimed naturally occurring nOMVs i.e., the judicial exceptions, into a practical application (Step 2A Prong Two: NO). No elements or claim limitations apply or use the exception(s) in any meaningful way and integrate the law of nature into a practical application. The limitation ‘composition’ merely indicates a field of use in which to apply the judicial exceptions and therefore fail to provide meaningful limits on the claims. The claims as a whole do not amount to significantly more than ‘products of nature’ (Step 2B: NO). Therefore, the claims are not directed to a patent eligible subject matter.
The rationale for this determination is formed in view of the 2019 PEG, the 2015 Update of the 2014 Interim Guidance on Patent Subject Matter Eligibility (79 FR 4618) (hereafter Interim Eligibility Guidance) dated 16 December 2014, the Life Sciences Examples issued in May 2016, and in view of Myriad v Ambry, CAFC 2014-1361, -1366, 17 December 2014. The unpatentability of laws of nature was confirmed by the U.S. Supreme Court in Mayo Collaborative Services v. Prometheus Laboratories, Inc., No. 10-1150 (March 20, 2012). The unpatentability of natural products was confirmed by the U.S. Supreme Court in Association for Molecular Pathology v. Myriad Genetics, Inc., 569 U. S. (June13, 2013).
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.
Claims 17 and 18 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Gasperini et al (Molecular & Cellular Proteomics, 17:205-215, 2018; of record).
Gasperini et al teach nOMV produced from B. pertussis strains PB536 and BP537 (see page 206, column 2, paragraph 2). nOMV were purified resuspended in Dulbecco’s phosphate-buffered saline. The nOMV of Gasperini et al anticipate the claimed nOMV as there is no apparent distinction between the two as the modified ribosomal protein, the modified gene or the modified operon of the genetically modified Gram-negative bacteria is not present in the nOMVs.
Regarding claims 17-18, these have been interpreted as product by process claims, and as such their patentability is determined by the structure of the product as claimed and not the process by which the product is obtained. See MPEP 2113. Once the Examiner provides a rationale tending to show that the claimed product appears to be the same or similar to that of the prior art, although produced by a different process, the burden shifts to applicant to come forward with evidence establishing an unobvious difference between the claimed product and the prior art product. In re Marosi, 710 F.2d 798, 802, 218 USPQ 289, 292 (Fed. Cir. 1983). "Where the claimed and prior art products are identical or substantially identical in structure or composition, or are produced by identical or substantially identical processes, a prima facie case of either anticipation or obviousness has been established." In re Best, 562 F.2d 1252, 1255, 195 USPQ 430, 433 (CCPA 1977). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Claims 1-7, 12 and 21 are rejected under 35 U.S.C. 102(a)(1) as being clearly anticipated by Boni et al (Journal of Bacteriology 182(20):5872-5879, 2000; of record).
Boni et al teach a mutation in E. coli rspA gene resulting in a mutation in the ribosomal protein S1. Boni et al teach the characterization of the suppressor ssyF29. The mutation is an IS10R element insertion in the 3” regions of the mutant rspA gene. This causes interruption of translation and causing synthesis of a truncated S1 lacking 92 C-terminal amino acids residues (see page 5872, column 2, last paragraph). Boni et al teach that despite the loss of the last S1 motif R4, the protein remains active in vivo for promoting initiation of protein synthesis on natural translation initiation regions (se page 5873, column 1, first paragraph). Inasmuch as, the E. coli with the suppressor ssyF29 mutation of the prior art has the claimed structural changes to the rspA gene and 30S ribosomal protein S1 it necessarily and inherently possesses the claimed phenotypic properties of increased nOMV production and culturing characteristics as claimed.
Since the Office does not have the facilities for examining and comparing applicant's product with the product of the prior art, the burden is on applicant to show a novel or unobvious difference between the claimed product and the product of the prior art. See In re Best, 562 F.2d 1252, 195 USPQ 430 (CCPA 1977) and In re Fitzgerald et al., 619 F.2d 67, 205 USPQ 594 (CCPA 1980). "When the PTO shows a sound basis for believing that the products of the applicant and the prior art are the same, the applicant has the burden of showing that they are not." In re Spada, 911 F.2d 705, 709, 15 USPQ2d 1655, 1658 (Fed. Cir. 1990).
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Patricia Duffy whose telephone number is (571)272-0855. The examiner can normally be reached 8:00 am - 4 pm.
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/Patricia Duffy/Primary Examiner, Art Unit 1645
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