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 .
Claims 15-34 have been presented for examination on the merits.
Objection to Specification
The disclosure is objected to because of the following informalities: The specification contains incomplete statements 1- on page 1, line 13 by reciting “acids, ….)” and 2- on page 7, line 8 by reciting “nanogels, …, and the like”. (Also see paragraphs [0002] and [0019] of the published version).
Appropriate correction is required.
Claim objection
Claims 21-22 and 32-33 are objected to because of the following informalities: the claims 21-22 and 32-33 capitalize terminology that is neither abbreviation nor trademarks/tradenames. 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.
Claim 34 is rejected under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, because the specification, while being enabling for delivering cell-impermeable material with or without an active agent to the cells, does not reasonably provide enablement for treating All skin or eye diseases as claimed. The specification does not enable any person skilled in the art to which it pertains, or with which it is most nearly connected, to make and use the invention commensurate in scope with these claims.
To be enabling, the specification of a patent must teach those skilled in the art how to make and use the full scope of the claimed invention without undue experimentation. In Genentech Inc. v. Novo Nordisk 108 F.3d 1361, 1365, 42 USPQ2d 1001, 1004 (Fed. Cir. 1997); In re Wright 999 F.2d 1557, 1561, 27 USPQ2d 1510, 1513 (Fed. Cir. 1993). See also Amgen Inc. v. Chugai Pharm. Co., 927 F.2d 1200, 1212, 18 USPQ2d 1016, 1026 (Fed. Cir. 1991); In re Fisher 427 F.2d 833, 839, 166 USPQ 18, 24 (CCPA 1970) and In re Wands 858 F.2d 731, 737, 8 USPQ2d 1400, 1404 (Fed. Cir. 1988).
There are many factors to be considered when determining whether there is sufficient evidence to support a determination that a disclosure does not satisfy the enablement requirement and whether any necessary experimentation is “undue”. See In re Wands, 858 F.2d 731, 737, 8 USPQ 2d 1400, 1404 (Fed. Cir. 1998). The court set forth the eight factors to consider when assessing if a disclosure would require undue experimentation. Citing Ex parte Forman, 230 USPQ 546, the court recited eight factors.
These factors include, but are not limited to:
1) The breadth of the claims,
2) The nature of the invention,
3) The state of the prior art,
4) The level of one of ordinary skill,
5) The level of predictability in the art,
6) The amount of direction provided by the inventor,
7) The existence of working examples,
8) The quantity of experimentation needed to male or use the invention based on the content of the disclosure.
(1 and 2) The breadth of the claims and the nature of the invention: The claims are broad. The claims are drawn to a method of treating a skin or eye disease the method comprising administering by topical or corneal administration, supramolecular polycationic materials and cell-impermeable molecules to a subject in need thereof.
(3 and 5) The state of the prior art and the level of predictability in the art: The art teaches methods of treating diseases such as skin or eye diseases by topical or corneal administration of a formulation comprising a specific therapeutic agent and a carrier. It is known in the art that diseases, such as skin or eye disease would fall under many categories of diseases and require specific treatments. There is no evidence in the Specification or prior art that a composition comprising a (any) supramolecular polycationic material and (any) cell-impermeable molecules can treat ANY skin or eye diseases as claimed here. Accordingly, the level of predictability of "all" diseases of skin or eye being treatable with the said method, in the art is very low.
(6 and 7) The amount of direction provided by the inventors and the existence of working examples: Applicants have provided in the specification disclosure regarding treating corneal diseases such as dry eye, corneal ulcer or infection by topical administration of the said materials, however it is disclosed that “When used in the treatment of corneal disorders, the cell-impermeable molecules, will include therapeutic ingredients for a corneal disease, for example, hyaluronic acid or its salt, chondroitin sulfate or its salt, the enzyme hyaluronidase other enzymes, anesthetics, vitamins, zinc, antibiotics, anti-allergic agents, carbamide, cytokinases, vasoconstrictors, anti-viral agents, anti-fungal agents, anti-inflammatory agents, lubricants and the like”. (See PG pub at [0080]). Similarly for treating a skin disease the Specification states that “In such application the cell-impermeable molecules will include therapeutic, dermatological, pharmaceutical, medical, and/or cosmetic compositions such as those that improve or eradicate itching, irritation, pain, inflammation, age spots, keratoses, wrinkles, and other blemishes or lesions of the skin. By way of example and not by way of limitation: analgesics, anesthetics, antiacne agents, antibacterial agents, anti-yeast agents, anti-fungal agents, antiviral agents, antibiotic agents, …., anti-dry skin agents, antiperspirants, etc, …” (See [0079]).
Additionally, the Specification defines the term ““cell-impermeable molecules” as used herein generally refers to any molecule often also referred to as “cargo” molecule, incapable of passively crossing the cell membrane of a cell. It typically includes macromolecular hydrophilic cargo such as RNAs, DNAs, proteins, glycoproteins, peptides, ribonucleoproteins” (See [0073]).
Thus, the Specification lacks any evidence or disclosure that an RNA, DNA, protein, glycoprotein, peptide or ribonucleoprotein is enabled to treat all skin or eye diseases. In view of the various different diseases known (and not yet known) which may or may not be treatable with the claimed method, further testing would be necessary to use the invention as broadly as claimed.
(8) The quantity of experimentation needed to make or use the invention bases on the content of the disclosure: The quantity of experimentation needed to make and use the invention based on the contents of the disclosure and the unpredictability asserted by the Applicant, is very high and not enabled by the specification.
Conclusion
For the forgoing reasons, the specification is not enabling for the scope of the claims.
In view of the unpredictability in the art, the lack of working examples, the excessive breadth of the claims and lack of guidance in the specification, it would require undue experimentation on the part of the person of skill in the art to practice the full scope of 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 (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 21-22, 25, 29 and 32-33 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.
Claims 21-22, 25 and 32-33 are indefinite for reciting “at least 2.5”, “at least 11 mV” and “at least 5 minutes”. These recitations render the claims indefinite because they include a one-sided range that encompasses infinity. That is at least … encompasses degrees and amounts that are neither envisioned nor possible.
Claim 25 is indefinite because it recites a composition for delivering cell-impermeable molecules into a cell cytosol, the composition comprising supramolecular polycationic materials. The claimed composition only comprises supramolecular polycationic materials. Thus, it is not clear how it delivers the cell-impermeable molecules into a cell cytosol.
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.
Claims 15, 18-21, 23-32 and 34 are rejected under 35 U.S.C. 102(a)(1) and (a)(2) as being anticipated by Raemdonck et al (WO 2018096057) or (US 20200197496) (below citations from the US document).
Raemdonck et al teach compositions comprising particles, the particle comprising one or more active agents and a proteolipid composition, the proteolipid composition consisting of a native surfactant-protein B (SP-B) or a peptide of the native SP-B, and one or more lipids; and whereby the composition delivers the one or more active agents across cellular membranes in the subject (See abstract and claim 1).
Regarding claims 15, 18 and 29, Raemdonck et al teach that the said particles or compositions can be used as a therapeutic medicine, for the cellular delivery of membrane-impermeable molecules in general, both macromolecular compounds but small molecules as well. Macromolecular compounds may include peptides, proteins, nucleic acids, oligosaccharides, polysaccharides, etc. (See [0032]). The particle can be a polymeric particle, more in particular a dextran nanogel, more in particular a cationic dextran nanogel (See [0012]).
Regarding claims 19-20 and 30-31, Raemdonck et al teach that the cationic agent may be a polycationic agent such as chitosan, protamines, or dextran which is functionalized with a reactive (meth)acrylate moiety and subsequently co-polymerized with a cationic (meth)acrylate monomer. The said cationic dextran nanogels prepared include dex-HEMA-co-TMAEMA nanogels (See [0035] and [0071]).
Regarding claims 21 and 32, Raemdonck et al teach synthesis of cationic dextran nanogels and loading siRNA, wherein dextran hydroxyethyl methacrylate (dex-HEMA) with a degree of substitution of 5.2 was used (See [0071]).
Regarding claims 23-24, Raemdonck et al teach dextran hydroxyethyl methacrylate (dex-HEMA) with a degree of substitution of 5.2 was dissolved in a solution and siRNA was added. No serum was included (See [0071]).
Regarding claim 25, Raemdonck et al teach synthesis of cationic dextran nanogels and loading siRNA, wherein the mixture is incubated for more than 15 minutes (See [0071]).
Regarding claim 26, Raemdonck et al teach that the said composition is capable of delivering the active agent across biological membranes (such as the cell membrane and/or the endosomal membrane), either in vivo, in vitro or ex vivo (See [0011], [0052] and [0056]).
Regarding claim 27, Raemdonck et al teach that that the cells may be cell lines (See [0072] and [0077]).
Regarding claims 28 and 34, Raemdonck et al teach that particles are useful for the prophylaxis and/or treatment of dermatologic diseases, cardiac diseases, endocrine diseases, pulmonary related diseases, ophthalmological diseases, etc, (See [0055]). The said compositions may be administered in a number of ways, e.g. by oral administration, by inhalation, by injection (into the blood stream or directly into a site requiring treatment), as topical use, etc, (See [0057]).
Claim Rejections - 35 USC § 103
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
Claims 15 and 18-34 are rejected under 35 U.S.C. 103 as being unpatentable over Raemdonck et al (WO 2018096057) or (US 20200197496) (below citations from the US document) as applied to claims 15, 29 and 34 above, and in further view of Raemdonck et al (Biodegradable dextran nanogels for RNA interference: Focusing on endosomal escape and intracellular siRNA delivery), herein Raemdonck et al 2.
Raemdonck et al ‘496’s teachings are delineated above and incorporated herein.
The reference lacks a specific disclosure on the zeta potential of the dextran nanogel. This limitation would have been obvious to incorporate in view of the teachings of Raemdonck et al 2.
Raemdonck et al 2 teach the successful therapeutic application of small interfering RNA (siRNA) largely relies on the development of safe and effective delivery systems that are able to guide the siRNA therapeutics to the cytoplasm of the target cell. Thus, the potential of biodegradable cationic dextran nanogels as siRNA carriers is evaluated. The nanogels are able to entrap siRNA with a high loading capacity, based on electrostatic interaction. Furthermore, it is shown that an efficient gene silencing requires the degradation of the nanogels. As the degradation kinetics of the nanogels can easily be tailored, these particles show potential for intracellular controlled release of short interfering RNA (See abstract).
Raemdonck et al 2 also state that the intracellular siRNA release mechanism is shown by performing control experiments with nondegradable dex-MA-co-TMAEMA nanogels. The accumulation of nanogel degradation products in the endosomal lumen is able to disrupt the vesicular membrane, possibly through an osmotic effect, thereby releasing active siRNA into the cytosol (See page 1412, 1st col. last para).
Regarding claims 22 and 33, Raemdonck et al 2, teach that adding TMAEMA to the aqueous dex-HEMA solution before emulsification enables copolymerization of this methacrylate monomer with dex-HEMA in the emulsion droplets, leading to nanogels with a cationic surface charge, as revealed from zeta-potential measurements (Table 1). Increasing the amount of TMAEMA increased the surface charge of the nanogels, indicating that more TMAEMA groups became incorporated in the nanogel network.
PNG
media_image1.png
296
479
media_image1.png
Greyscale
(See Page 1407).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Raemdonck et al 2 with Raemdonck et al ‘496 to arrive at the instant invention. It would have been obvious to do so because both references are directed to cellular delivery of a cell-impermeable compound such as siRNA via a carrier including a polycationic material such as dextran nanogel. While Raemdonck et al ‘496 is silent with regard to the zeta potential of the dextran nanogel, Raemdonck et al 2 teach that measuring and maintaining the zeta potential of the said polycationic nanogel is important in determining the surface charge of the particle specially at cell membrane.
In other words, the claims would have been obvious because the technique for improving a particular formulation was part of the ordinary capabilities of a person of ordinary skill in the art, in view of the teaching of the technique for improvement in other situations. That is measuring the zeta potential and mainlining the zeta potential of the said nanogels provides for an optimum result in cellular delivery.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 15-17 are rejected under 35 U.S.C. 103 as being unpatentable over Raemdonck et al (WO 2018096057) or (US 20200197496) (below citations from the US document) as applied to claim 15 above, and in further view of Stewart et al (In vitro and ex vivo strategies for intracellular delivery).
Raemdonck et al ‘496’s teachings are delineated above and incorporated herein.
The reference lacks a specific disclosure on the sequential delivery of supramolecular polycationic material and cell-impermeable molecules. This modification would have been obvious in view of the teachings of Stewart et al.
Stewart et al teach that intracellular delivery of materials has become a critical component of genome-editing approaches, ex vivo cell-based therapies, and a diversity of fundamental research applications. The study focuses on membrane-disruption-based delivery methods and the transformative role of nanotechnology, microfluidics and laboratory-on-chip technology in advancing the field (See abstract).
Regarding claims 16-17, Stewart et al, teaches that intracellular delivery can be achieved by a range of carrier-based or membrane-disruption-based techniques. Unlike carriers, membrane-disruption-based approaches are less dependent on cargo properties, being able to deliver almost any submicrometre material dispersed in solution. The ability to rapidly switch membrane-perturbing effects on and off enables temporal control and rapid, almost instantaneous delivery. A further strength of membrane-disruption techniques in vitro and ex vivo is the broad range of cell types and materials that can be addressed. Membrane-disruption-based approaches may furthermore be combined with carriers to synergize the strengths of both, such as by delivering a nuclear-targeted DNA lipoplex to the cytoplasm. Membrane-disruption-based delivery has also enabled several protein-delivery applications, featuring antibodies, etc, (See page 185, 1st col and paragraph bridging pages 186-187).
It would have been prima facie obvious to a person of ordinary skilled in the art at the time the invention was made to have combined the teachings of Stewart et al with Raemdonck et al ‘496 to arrive at the instant invention. It would have been obvious to do so because both references are directed to cellular delivery of a cell-impermeable compound such as siRNA. While Raemdonck et al ‘496 is mostly focused on such delivery using polycationic material as the carrier and suggest simultaneous of the two materials to the cell, Stewart et al teach that the cell delivery can be either by a carrier material or by membrane disruption. Stewart et al also discloses the advantages of membrane-disruption methods including less dependent on cargo properties, being able to deliver almost any submicrometre material dispersed in solution.
In other words, the claims would have been obvious because a person of ordinary skill has good reasons to pursue the known options within his or her technical grasp. If this leads to the anticipated success, it is likely the product not of innovation but of ordinary skill and common sense. That is one of ordinary skill in the art is more than motivated to look into other and possibly better options for a disclosed method with reasonable expectation of success.
From the combined teaching of the cited references, one of ordinary skill in the art would have had a reasonable expectation of success in producing the claimed invention. Therefore, the invention, as a whole, would have been prima facie obvious to one of ordinary skill in the art at the time the invention was made.
Claims 15-34 are rejected.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to Mina Haghighatian whose telephone number is (571)272-0615. The examiner can normally be reached M-F, 7-5 EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Sue X. Liu can be reached at 571-272-5539. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
/Mina Haghighatian/
Mina Haghighatian
Primary Examiner
Art Unit 1616