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 .
Applicants filed a Preliminary Amendment on July 26, 2023, in which they canceled claims 11, 15, 18-21, 24-27, and 29-41 and amended claims 1-4, 7-8, 10, 12-14, 16-17, 22-23, and 28. Claims 1-10, 12-14, 16-17, 22-23, and 28 are pending in this application and are under examination.
Information Disclosure Statement
The Information Disclosure Statements filed November 28, 2024 (6) have been considered.
Specification
Applicant is reminded of the proper language and format for an abstract of the disclosure.
The abstract should be in narrative form and generally limited to a single paragraph on a separate sheet within the range of 50 to 150 words in length. The abstract should describe the disclosure sufficiently to assist readers in deciding whether there is a need for consulting the full patent text for details.
The language should be clear and concise and should not repeat information given in the title. It should avoid using phrases which can be implied, such as, “The disclosure concerns,” “The disclosure defined by this invention,” “The disclosure describes,” etc. In addition, the form and legal phraseology often used in patent claims, such as “means” and “said,” should be avoided.
The use of the terms TALEN® at paragraphs [0009], [0071], and [0118], and ALEXA® at paragraph [0076], which are trade names or marks used in commerce, has been noted in this application. The terms should be accompanied by the generic terminology; furthermore the term should be capitalized wherever they appear or, where appropriate, include a proper symbol indicating use in commerce such as ™, SM , or ® following the term.
Although the use of trade names and marks used in commerce (i.e., trademarks, service marks, certification marks, and collective marks) are permissible in patent applications, the proprietary nature of the marks should be respected and every effort made to prevent their use in any manner which might adversely affect their validity as commercial marks.
The disclosure is objected to because of the following informalities:
All genus and species names should be italicized.
Appropriate correction is required.
Claim Objections
Claim 28 is objected to because of the following informalities:
At claim 28, line 4, “mega nuclease” should be changed to “meganuclease.”
Appropriate correction is required.
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 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 1-10, 12-14, 16-17,and 22 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.
The MPEP states that the purpose of the written description requirement is to ensure that the inventor had possession, as of the filing date of the application, of the specific subject matter later claimed by him. The courts have stated:
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 (Fed. Cir. 1997); In re Gostelli, 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; Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
Further, for a broad generic claim, the specification must provide adequate written description to identify the genus of the claim. In Regents of the University of California v. Eli Lilly & Co., the court stated:
A written description of an invention involving a chemical genus, like a description of a chemical species, "requires a precise definition, such as by structure, formula, [or] chemical name," of the claimed subject matter sufficient to distinguish it from other materials. Fiers v. Revel, 984 F.2d at 1171,25 USPQA2d, 1601; In re Smyth, 480 F.2d 1376,1383, 178 USPQ 279,284 (CCPA 1973) ("In other cases, particularly but not necessarily, chemical cases, where there is an unpredictability in performance of certain species or subcombinations other than those specifically enumerated, one skilled in the art may be found not to have been placed in possession of a genus...") Regents of the University of California v. Eli Lilly & Co., 43 USPQ2d 1398.
The MPEP further states that if a biomolecule is described only by a functional characteristic, without any disclosed correlation between function and structure of the sequence, it is "not a sufficient characteristic for written description purposes, even when accompanied by a method of obtaining the claimed sequence." MPEP § 2163. The MPEP does state that, for a generic claim, the genus can be adequately described in the disclosure presents a sufficient number of representative species that encompass the genus. MPEP § 2163. If the genus has a substantial variance, the disclosure must describe a sufficient variety of species to reflect the variation within that genus. See MPEP § 2163. Although the MPEP does not define what constitutes a sufficient number of representative species, the courts have indicated what does not constitute a representative number of species to adequately describe a broad genus. In Gostelli, the courts determined that the disclosure of two chemical compounds within a subgenus did not describe that subgenus. In re Gostelli, 872 F.2d at 1012, 10 USPQ2d at 1618. The MPEP lists factors that can be used to determine if sufficient evidence of possession has been furnished in the disclosure of the application. These include: (1) Actual reduction to practice, (2) Disclosure of drawings or structural chemical formulas, (3) Sufficient relevant identifying characteristics (such as: i. Complete structure, ii. Partial Structure, iii. Physical and/or chemical properties, iv. Functional characteristics when coupled with a known or disclosed structure, and v. Correlation between function and structure), (4) Method of making the claimed invention, (5) Level of skill and knowledge in the art, and (6) Predictability in the art.
A "representative number of species" means that the species, which are adequately described, are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. This disclosure of only one or a few species encompassed within a genus adequately describes a claim directed to that genus only if the disclosure indicates that the patentee has invented species sufficient to constitute the gen[us]." See Enzo Biochem, 323 F.3d at 966, 63 USPQ2d at 115; Noelle v. Lederman, 355 F.3d, 1343, 1350, 69 USPO2d 1508, 1514 (Fed. Cir. 2004) ("[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated."). In addition, it has been well known that minor structural differences even among structurally related compounds can result in substantially different biology, expression, and activities. The instant claims require that a compound is delivered to a cell having a cell wall. The claims further list a vast number and type of compounds that may be delivered to the cell, including transposons, plasmids, plastids, polypeptide-nucleic acid complexes, lipid-nucleic acid complexes, cation-nucleic acid complexes, polypeptides/peptides, small molecules, nanoparticles, liposomes, or fluorescently tagged molecules. The rejected claims thus comprise a genus of compounds, which may be any type of compound or complex, and of any size. The specification and claims further recite that the compounds can be nucleic acids or a Cas9 protein and guide and/or donor DNA, a transposase/transposon, a TALEN®, a zinc finger protein, a meganuclease, a CRE recombinase, a FLP recombinase, an R recombinase, an integrase, a histone acetyltransferase, a deacetylase, a methyltransferase, a demethylase, an antibody or a transcription factor (claim 28).
To provide adequate written description and evidence of possession of a claimed genus, the specification must provide sufficient distinguishing identifying characteristics of the genus. The factors to be considered include disclosure of a complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, and any combination thereof. The specification provides data regarding the detection of only a few specific compounds, such as fluorescent dextran particles and plasmid DNA encoding nourseothricin N-acetyl transferase (NAT).
However, it is impossible for one to extrapolate from the limited specific compounds that are able to be delivered to cells having cell walls, which include fluorescent particles and plasmids that can express an enzyme or protein. The prior art does not appear to offset the deficiencies of the instant specification. For example Hallow et al. (Biotechnology and Bioengineering 846-854 (2008), and cited in the Information Disclosure Statement filed November 28, 2023) disclose that, although passing a cell through a constriction (high shear stress) allows for delivery of some molecules, such as calcein, dextrans, and bovine serum albumin by removal of plasma membrane sections, little is known about the dependence of cell permeabilization as a function of imposed shear stress (abstract and page 847, column 1, second full paragraph). Hallow further discloses that controlled flow through microchannels (e.g., microfluidic devices), while allowing intracellular delivery of small and large molecules, notes that intracellular uptake is only by a fraction of cells and that there is some loss of cell viability (page 853, paragraph bridging columns 1 and 2). However, Hallow does not disclose the delivery of compounds to cells having cell walls.
Therefore, the description of the limited sources of compounds that are deliverable to a cell having a cell wall is not sufficient to support the genus of such a vast number and types of compounds. Vas-Cath Inc. v. Mahurkar, 19USPQ2d 1111, clearly states "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 Vas-Cath at page 1117.) The specification does not "clearly allow persons of ordinary skill in the art to recognize that [he or she] invented what is now is claimed." (See Vas-Cath at page 1116). As discussed above, the skilled artisan cannot envision all of the myriad compounds that might, or might not be deliverable to a cell using the instantly claimed method. Adequate written description requires more than a mere statement that it is part of the invention and reference to a potential antibody-DNA conjugate. The compound itself is required. See Fiers v. Revel, 25USPQ2d 1601 at 1606 (CAFC 1993) and Amgen Inc. v. Chugai Pharmaceutical Co. Ltd., 18USPQ2d 1016. Therefore, the skilled artisan would have reasonably concluded applicants were not in possession of the claimed invention for claims 1-8 and 10.
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 1-10, 12-14, 16-17, 22-23 and 28 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.
At claim 1, lines 5-6, it is not clear if the compound is contacted with the cell or if the perturbation is contacted with the cell. It is suggested that “the compound enters the cell through the perturbation when contacted with the cell” be changed to “the compound enters the cell, when contacted with the cell, through the perturbation.”
Claims 7-10, 12-14, 16-17, 22-23, and 28 depend from claim 1, and are therefore included in this rejection.
At claim 2, lines 4-6, it is not clear if the compound is contacted with the cell or if the perturbation is contacted with the cell. It is suggested that “the compound enters the cell through the perturbation when contacted with the cell” be changed to “the compound enters the cell, when contacted with the cell, through the perturbation.”
At claim 3, lines 5-6, it is not clear if the compound is contacted with the cell or if the perturbation is contacted with the cell. It is suggested that “the compound enters the cell through the perturbation when contacted with the cell” be changed to “the compound enters the cell, when contacted with the cell, through the perturbation.”
Claims 4-6 depend from claim 3, and are therefore included in this rejection.
Claim 12 recites the limitation "the cell diameter" in line 2. There is insufficient antecedent basis for this limitation in the claim.
At claim 23, it is not clear how the nucleic acid “comprises” a DNA, recombinant DNA, cDNA, genomic DNA, RNA, siRNA, mRNA, miRNA, lncRNA, tRNA, shRNA, or self-amplifying mRNA. It is suggested that “comprises” be changed to “is.”
Claim 28 contains the trademark/trade name TALEN®. Where a trademark or trade name is used in a claim as a limitation to identify or describe a particular material or product, the claim does not comply with the requirements of 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph. See Ex parte Simpson, 218 USPQ 1020 (Bd. App. 1982). The claim scope is uncertain since the trademark or trade name cannot be used properly to identify any particular material or product. A trademark or trade name is used to identify a source of goods, and not the goods themselves. Thus, a trademark or trade name does not identify or describe the goods associated with the trademark or trade name. In the present case, the trademark/trade name is used to identify/describe the transcription activator-like effector nuclease, and, accordingly, the identification/description is indefinite.
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 1-6, 8-10, 12-14, 16-17, 22-23, and 28 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,613,759.
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘759 patent and the instant application claim methods of delivering compounds to a cell having a cell wall.
Regarding claims 1-3 and 8, the ‘759 patent claims a method of delivering a compound into a cell having a cell wall that has all or part of the cell wall removed by passing a cell suspension through a constriction, which deforms the cell by causing a perturbation, such that the compound enters the cell through the perturbation at the time the cell is contacted with the compound, and where the constriction is a pore or contained within a pore (claims 1 and 15).
Regarding claims 4-5, the ‘759 patent claims that removing all or part of the cell wall comprises treating the cell with an enzyme, heat, or ultrasound (claim 16).
Regarding claim 6, the ‘759 patent claims that the enzyme is one or more of cellulase, pectinase, xylanase, lysozyme, or chitinase (claim 17).
Regarding claim 9, the ‘759 patent claims that the pore is contained in a surface (claim 2).
Regarding claim 10, the ‘759 patent claims that the surface is a filter or a membrane (claim 3).
Regarding claim 12, the ‘759 patent claims that the constriction comprises a size which is about 20% to about 99% of the diameter of the cell, which is interpreted as the size of the constriction being a function of the cell diameter (claim 4).
Regarding claim 13, the ‘759 patent claims that the constriction size is about 20%, about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about 90%, or 99% of the cell diameter (claim 5).
Regarding claim 14, the ‘759 patent claims that the cell suspension is a mixed cell population or a purified cell population (claim 6).
Regarding claim 16, the ‘759 patent claims that the cell is a plant cell, a yeast cell, a fungal cell, an algal cell, or a prokaryotic cell (claim 7).
Regarding claim 17, the ‘759 patent claims that the plant cell is a crop, model, ornamental, vegetable, leguminous, conifer, or grass plant cell; that the yeast cell is Candida, Hansenula, Kluyveromyces, Pichia, Saccharomyces, Schizosaccharomyces, or Yarrowia strain cell; that the fungal cell is an Acremonium, Aspergillus, Fusarium, Humicola, Mucor, Myceliophthora, Neurospora, Penicillium, Scytalidium, Thielavia, Tolypocladium, or Trichoderma strain cell; that the prokaryotic cell is a Bacillus coagulans, Bacteroides fragilis, Bacteroides melaninogenicus, Bacteroides oralis, Bifidobacterium bifidum, Bifidobacterium breve, Bifidobacterium infantis,Bifidobacterium lactis, Bifidobacterium longum, Carboxydocella sp., Clostridium perfringens, Clostridium septicum, Clostridium tetani, Corynebacterium glutamicum, Enterobacteriaceae, Enterococcus faecalis, Erwinia chrysanthemi, Faecalibacterium prausnitzii, Lactobacillus acidophilus, Lactobacillus brevis, Lactobacillus bulgaricus, Lactobacillus fermentum,Lactobacillus gasseri, Lactobacillus paracasei, Lactobacillus plantarum, Lactobacillus reuteri, Lactobacillus rhamnosus, Lactobacillus salivarius, Lactobacillus sp., Pediococcus acidilactici, Peptococcus sp., Peptostreptococcus sp., Propionibacterium freudenreichii, Proteus mirabilis, Pseudomonas aeruginosa, Rhodopseudomonas capsulata, Salmonella enteritidis, Staphylococcus aureus, Streptococcus faecium, Streptococcus lactis, Streptococcus salivarius, Streptococcus thermophilus, Vibrio furnissii, Caldicellulosiruptor saccharolyticus, Xanthomonas campestris, cyanobacteria, Escherichia, Enterobacter, Azotobacter, Erwinia, Bacillus, Pseudomonas, Klebsiella, Proteus, Salmonella, Serratia, Shigella, Rhizobia, Vitreoscilla, Synechococcus, Synechocystis, or Paracoccus cell; or that the algal cell is a Chlorophyceae, Bacillariophyceae, Eustigmatophyceae, or Chrysophyceae cell (claim 8).
Regarding claim 22, the ‘759 patent claims that the compound is a nucleic acid, a transposon, a plasmid, a plastid, a polypeptide-nucleic acid complex, a lipid-nucleic acid complex, a cation-nucleic acid complex, a polypeptide or peptide, a small molecule, a nanoparticle, a liposome, or a fluorescently tagged molecule (claims 11-12).
Regarding claim 23, the ‘759 patent claims that the nucleic acid is DNA, recombinant DNA, cDNA, genomic DNA, RNA, siRNA, mRNA, lncRNA, tRNA, shRNA, or self-amplifying RNA (claim 10).
Regarding claim 28, the ‘759 patent claims that the compound can be a Cas9 protein and guide RNA or donor DNA, a nucleic acid encoding the Cas9 protein and guide RNA/donor DNA, a transposase protein and nucleic acid comprising a transposon, a TALEN®, a zinc finger nuclease, a meganuclease, a CRE recombinase, a FLP recombinase, an R recombinase, an integrase or transposase, a histone acetyltransferase, a deacetylase, a methyltransferase, a demethylase, an antibody, or a transcription factor (claims 13-14 and 24-25).
Thus, the claims are not deemed to be patentably distinct.
Claim 7 is rejected on the ground of nonstatutory double patenting as being unpatentable over claims 1-25 of U.S. Patent No. 11,613,759, as applied to claims 1-6, 8-10, 12-14, 16-17, 22-23, and 28 above, and in view of Sharei et al. (110(6) Proceedings of the National Academy of Sciences USA 2082-2087 (2013), and cited in the Information Disclosure Statement filed November 28, 2023).
Although the claims at issue are not identical, they are not patentably distinct from each other because both the ‘759 patent and the instant application claim methods of delivering compounds to a cell having a cell wall.
The ‘759 patent does not claim that the constrictions are contained within a microfluidic channel.
However, Sharei discloses methods of intracellular delivery of various compounds into cells using microfluidic devices that allow the cells to pass through constrictions that are 30% to 80% smaller than the cell diameter (abstract).
It would have been obvious to one with ordinary skill in the art before the effective filing date of the claimed invention that the method of the ‘759 patent could be performed in Sharei’s microfluidic device because both the pores of the ‘759 patent and the microfluidic device of Sharei both are known to introduce perturbations into cells via passing the cells through a constriction. As such, one of ordinary skill in the art would have had a predictable and reasonable expectation of success in using either well-known method of constrictiong.
Conclusion
The prior art made of record and not relied upon is considered pertinent to applicant's disclosure.
Sharei et al. (Sharei II, 81 Journal of Visualized Experiments e50980, 1-9 (2014), and cited in the Information Disclosure Statement filed November 28, 2024) disclose methods of intracellular delivery of various compounds into cells using microfluidic devices that allow the cells to pass through constrictions (abstract).
Any inquiry concerning this communication or earlier communications from the examiner should be directed to NANCY J LEITH whose telephone number is (313)446-4874. The examiner can normally be reached Monday - Thursday 8:00 AM - 6:30 PM.
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If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, NEIL HAMMELL can be reached at (571) 270-5919. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
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NANCY J. LEITH
Primary Examiner
Art Unit 1636
/NANCY J LEITH/Primary Examiner, Art Unit 1636
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