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 .
Continued Examination Under 37 CFR 1.114
A request for continued examination under 37 CFR 1.114, including the fee set forth in 37 CFR 1.17(e), was filed in this application after final rejection. Since this application is eligible for continued examination under 37 CFR 1.114, and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114. Applicant's submission filed on 06/02/2026 has been entered.
Information Disclosure Statement
Information disclosure statement (IDS) filed on 5/20/2026 is comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609. Accordingly, they have been placed in the application file and the information therein has been considered as to the merits.
Status of the application
Receipt of applicant’s remarks filed on 06/02/2026 and 06/19/2026 are acknowledged.
In light of applicants arguments previous 103 rejections are withdrawn. To clarify applicants remarks, a new grounds of rejection is made. The rejection is based on the different interpretation of the previously applied references and newly found art, which provides an explanation of the rejection. See the rejection below.
Examiner also acknowledges applicants filed declaration. See examiner’s response below.
In addition, a new 112(a) written description rejection is made.
Response to Arguments
Applicants argue that Ma-Lauer’s own experimental data demonstrate that exogenous p53 is rapidly degraded in the precise cellular environment the Examiner proposes to treat.
To overcome degradation of p53, the cited art teaches advantages of incorporating vesicles with p53. Therefore, a skilled person in the art would be motivated to make p53 conjugated to vesicles, or cell derived vesicles comprising p53.
Applicants argue that Tendler contains to antiviral data, no teachings of any antiviral application, and no teaching that vesicle encapsulation protects p53 from virus-induced degradation.
This one is addressed in the rejection. So, Tendler teaches that a therapeutically effective amount of cell derived vesicles obtained from cells expressing at least 0.5 % endogenous wild-type p53 protein of the total cellular proteins and not expressing recombinant p53 protein, for use in treating a disease, disorder or condition associated with a mutant or a nonfunctional p53 protein in a subject in need thereof. The disease is interpreted as viral infection.
Applicants argue that Alone-Grinstein or Lazo, does not supply the missing teachings and affirmatively undermines the generalization the examiner attempts to draw.
The purpose of Aloni-Grinstein and Lazo is to show nexus between p53 and DNA viral infections.
With regard to filed declaration, it is not clear what applicants indent to prove from the shown data. Is it comparative data with and without cell derived vesicles? or comparative data of EXOp53 with cell derived vesicles comprising p53?
If it is one or both of above, still claims are obvious over the cited art. Tendler teach cell-derived vesicles comprising p53 and, Irvine and Adrienne teach advantages of vesicles in drug delivery.
Claim Rejections - 35 USC § 112 – 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, 3, 5-6, 8, 12-13, 16, 20-21, 24-25, 28, 30-31 and 38 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 for the claimed method. 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 pre-AIA the inventor(s), at the time the application was filed, had possession of the claimed invention.
The rejection is based on the requirement(s), i.e., the guidelines provided by the MPEP 2163.04. These are listed below:
(A) identify the claim(s) limitations at issue, and
(B) establish a prima facie case by providing reasons why a person skilled in the art at the time the application was filed would not have recognized that the inventor was in possession of the invention as claimed in view of the disclosure of the application as filed. The MPEP 2163 further provided or expanded the guidelines for the written description requirements.
(A) IDENTIFY THE CLAIM LIMITATIONS AT ISSUE:
Claim 1 is drawn to a method of treating a viral infection or induced cell cycle arrest and/or apoptosis of a virally infected cell, in a subject in need thereof, comprising: (a) selecting a subject who has tested positive for the viral infection; and (b) administering to the subject a therapeutically effective amount of cell- derived vesicles comprising wild-type p53, thereby treating the viral infection in the subject.
Independent claim is broad with respect to all possible viral infections, in all possible subjects, with all possible administrations with all possible dosage amounts, wherein subject can be a cell or human or non-human.
Dependent claims define pathogen of viral disease, and cell derived vesicles and subject etc.
To support above broadly claimed subject matter, specification described (i) in vitro proof of concept of the antiviral efficacy of p53-comprising cell-derived vesicles in Vero E6 cells infected by SARS-CoV2, (ii) antiviral efficacy of p53-comprising cell-derived vesicles on SARS-CoV-2 in Vero E6 cells infected by SARS-CoV2, and (iii) in-vivo proof of concept of the antiviral efficacy of p53-comprising cell-derived vesicles in transgenic mice.
So, shown data is limited to SARS-CoV2 and subject is limited to Vero E6 cells and transgenic mice. However, no description is provided on ‘how the shown data can be extrapolated to the claimed genus in the claimed subject matter’.
Applicants can claim as broadly as possible for the claimed invention. However, if there is a variability in the genus or broadly claimed subject matter, and if the variability expects unpredictability for the claimed subject matter, then specification must describe the genus with divergent species, so that a skilled person in the art can understands claimed invention and can reproduce applicants claimed invention. In this case, at least viruses and cell types are probably one of the most unpredictable areas of biotechnology and consequently, the effects of dissimilarities and function cannot be predicted. So, the absence of description, for representative species for divergent subject matter, makes the invention unpredictable, and cannot be envisioned by a skilled person in the art.
The issue is, will cell-derived vesicles comprising p53 capable of treat all possible viral infections, with all possible mode of administrations? Do applicants provide enough description for all the variables in the broadly claimed subject matter and their association towards the end property, so that a skilled person in the art understands the claimed invention?
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 "level of skill and knowledge in the art, partial structure, physical and/or chemical properties, functional characteristics alone or coupled with a known or disclosed correlation between structure and function, and the method of making the claimed invention. Disclosure of any combination of such identifying characteristics that distinguish the claimed invention from other materials and would lead one of skill in the art to the conclusion that the applicant was in possession of the claimed species is sufficient" (MPEP 2163).
A claimed genus may be satisfied through sufficient description of a representative number of species or disclosure of relevant, identifying characteristics such as functional characteristics coupled with a known or disclosed correlation between function and structure. See MPEP 2163 II(A)(3)(a)(ii).
The number of species that describe the genus must be adequate to describe the entire genus. However, if there is substantial variability, a large number of species must be described. However, no such description is provided in the specification.
(B) ESTABLISH A PRIMA FACIE CASE BY PROVIDING REASONS WHY A PERSON SKILLED IN THE ART AT THE TIME THE APPLICATION WAS FILED WOULD NOT HAVE RECOGNIZED THAT THE INVENTOR WAS IN POSSESSION OF THE INVENTION AS CLAIMED IN VIEW OF THE DISCLOSURE OF THE APPLICATION AS FILED:
The further analysis for adequate written description considers, see MPEP 2163, the following:
(A) Determine whether the application describes an actual reduction to practice of the claimed invention:
Not provided. Description is limited SARS-CoV2 and subject is limited to Vero E6 cells and transgenic mice. No description is provided on ‘how the shown data can be extrapolated to the claimed genus in the claimed subject matter’. The dosage range information and mode of administrations have not been provided, further, it is completely generic.
So, the provided data is very limited. Accordingly, applicants failed to describe actual reduction to practice of the claimed invention.
(B) If the application does not describe an actual reduction to practice, determine whether the invention is complete as evidenced by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole:
Fig.1-4 are theoretical description of p53 induction and is properties in viral infections. No specific viral infection is described. Moreover it is generic.
Fig.5-7 describes efficacy and specificity of p53 comprising cell-derived vesicles on cancer cells. Not related to claimed subject matter.
Fig. 8 describes in vitro assays carried out as a proof-of-concept illustrating the antiviral efficacy of p53 comprising cell-derived vesicles. Description is limited to SARS-CoV2 and Vero E6 cells.
Fig. 9 describes in-vivo proof of concept of the antiviral efficacy of p53-comprising cell-derived vesicles in transgenic mice. Description is limited to SARS-Co-V2 and transgenic mice.
So, as evidenced from the above description of drawings, it is clear that the claimed invention is not complete by a reduction to drawings or structural chemical formulas that are sufficiently detailed to show that applicant was in possession of the claimed invention as a whole.
(C) If the application does not describe an actual reduction to practice or reduction to drawings or structural chemical formula as discussed above, determine whether the invention has been set forth in terms of distinguishing identifying characteristics, such as structure/function correlations, as evidenced by other descriptions of the invention that are sufficiently detailed to show that applicant was in possession of the claimed invention:
The specification fails to describe a correlation between structure and function for the claimed divergent genus. In this case, treating all possible viral infections in all possible subjects with all possible mode of administrations etc. Different cell types and different viruses have different properties towards different drugs. There is no single or common receptor on all cell types for viruses. Each virus has varying pathological manifestations and require different treatment modes.
For example, Smith [Science, vol.304, 9 April 2004, 237-242] teaches that to infect a cell, a virus must first attach itself to the surface of a cell. The molecules to which viruses bind constitute a diverse collection of cellular proteins, carbohydrates, and lipids. They differ from one virus to the next, and they range from abundant and ubiquitous to rare and cell specific. Some of them merely serve as attachment factors that concentrate viruses on the cell's surface. Others are true receptors in that they not only bind viruses but are also responsible for guiding the bound viruses into endocytic pathways and for transmitting signals to the cytoplasm. Receptors can also serve as cues that induce conformational changes that lead to membrane fusion and penetration. The identity and distribution of attachment factors and receptors determines to a large extent which cell types, tissues, and organisms a virus can infect. [see section Receptors and Attachment Factors in page 237].
There is also unpredictability in the mode of administration, for example, Bruno et al [Ther Deliv, 2013 Nov, 4(11), 1443-1467] teach the following:
While the peptide and protein therapeutic market has developed significantly in the past decades, delivery has limited their use. Although oral delivery is preferred, most are currently delivered intravenously or subcutaneously due to degradation and limited absorption in the gastrointestinal tract. Therefore, absorption enhancers, enzyme inhibitors, carrier systems and stability enhancers are being studied to facilitate oral peptide delivery. Additionally, transdermal peptide delivery avoids the issues of the gastrointestinal tract, but also faces absorption limitations. Due to proteases, opsonization and agglutination, free peptides are not systemically stable without modifications. This review discusses oral and transdermal peptide drug delivery, focusing on barriers and solutions to absorption and stability issues. Methods to increase systemic stability and site-specific delivery are also discussed. [See abstract and whole article].
In view of above evidences, applicants have claimed unlimited range of viral infections, subjects, and mode of administrations etc., and so, a skilled person in the art can expect unpredictability in the broadly claimed genus. There are no physical/chemical/structural features that applicants have tied to this property in a relevant teaching manner, making it impossible for an individual of ordinary skill in the art to determine which of the very large genus of claimed subject matter would be effective for the claimed method. Without a correlation between structure and function, the claims do little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement.
Applicants have failed to provide guidance or data or evidence as to how the skilled artisan would be able to extrapolate from the disclosure species to make and possibly use of the claimed invention. “A description of what a material does, rather than of what it is, usually does not suffice." Rochester, 358 F 3d at 923; Eli Lilly, 119 at 1568. Instead, the “disclosure must allow one skilled in the art to visualize or recognize the identity of the subject matter purportedly described.”
Vas-Cath Inc. Mahurkar, 19 USPQ2d 1111, makes clear the "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).
Accordingly, it is deemed that the specification fails to provide adequate written description for the genus of the claimed subject matter and does not reasonably convey to one skilled in the relevant art that the inventors had possession of the entire scope of the claimed invention.
Claim Rejections - 35 USC § 103
In the event the determination of the status of the application as subject to AIA 35 U.S.C. 102 and 103 (or as subject to pre-AIA 35 U.S.C. 102 and 103) is incorrect, any correction of the statutory basis for the rejection will not be considered a new ground of rejection if the prior art relied upon, and the rationale supporting the rejection, would be the same under either status.
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102 of this title, 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 set forth in Graham v. John Deere Co., 383 U.S. 1, 148 USPQ 459 (1966), that are applied for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
I. Claims 1, 5-6, 8, 12-13, 16, 20-21, 24-25, 28, 30-31 and 38 are rejected under 35 U.S.C. 103 as being unpatentable over Ma-Lauer (PNAS, 2016, Aug 12, E5192-E5201; see applicants filed IDS dated 12/04/2022) in view of Tendler (WO 2018/173059 A1; see applicants filed IDS dated 12/04/2022), Adrienne (US 2017/0246288 A1), Irvine (US 2018/0360952 A9), Aloni-Grinstein (Cancers, 2018, 10, 178, 1-11; see applicants filed IDS dated 12/04/2022) and Lazo (Rev.Med.Virol., 2011, 21, 285-300).
For claim 1:
Ma-Lauer teaches a method, wherein p53 inhibits replication of SARS-CoV, wherein the method comprises infecting human ACE2-transgenic p53-expressing HCT116 cells (HCT116/ACE2 p53+/+) as well as p53 knockout cells (HCT116/ACE2 p53−/−) with SARS-CoV, and viral replication was monitored by real-time PCR., SARS-CoV grew to an ∼1,000-fold higher titer in p53−/− cells compared with p53+/+ [see abstract, section P53 Inhibits Replication of a SARS-CoV in pages E5196-E5197 and Fig.6].
Above is interpreted as a method of treating viral infection, wherein the subject is cells. Alternatively, p53 is shown to inhibit replication of SARS-CoV, and so a skilled person in the art would be motivated to extrapolate administration of p53 to treat viral infection in animals.
The difference is that Ma-Lauer is silent on ‘cell-derived vesicles comprising wild-type p53’.
The following art and the reasoning cures the above deficiency:
Tendler teaches cell derived vesicles comprising an active wild-type p53, wherein microvesicles serve as signaling payloads containing cell-specific collections of proteins, lipids and genetic material that are transported to other cells where they can alter cell' s function and physiology. Exosomes, microvesicles of about 40-200 nm in diameter, have pleiotropic biological functions, including immune response, antigen presentation, intracellular communication, and cell to cell transfer of RNA and proteins. Exosomes are typically formed when cellular compartments known as multivesicular endosomes (MVE) or multivesicular bodies (MVB) bud inward to form small internal vesicles containing proteins, mRNAs and miRNA from the cytoplasm. These internal vesicles are released as exosomes when MVE fuse with the cell membrane or, alternatively fuse with lysosomes. Tendler further states that recently, experiments with exosomes as means of chemo- and other therapy delivery vehicles were reported, e.g. as means for delivery of drugs, microRNAs, siRNAs, and antigens to target recipient cells in order to treat tumorigenesis or metastasis [See page 1 and Summary of Invention].
Tendler further teaches that Normal p53 is inactivated by interaction with overexpression of MDM2/MDM4 or viral proteins causing its degradation. High levels of p53 is found in the cytoplasm of corneal epithelium cells, wherein high levels of p53 are accompanied by absence of MDM2. [see page 2].
Tendler further teaches that a therapeutically effective amount of cell derived vesicles obtained from cells expressing at least 0.5 % endogenous wild-type p53 protein of the total cellular proteins and not expressing recombinant p53 protein, for use in treating a disease, disorder or condition associated with a mutant or a nonfunctional p53 protein in a subject in need thereof. The disease is interpreted as viral infection.
Therefore, a skilled person in the art would be motivated to replace p53 in the teachings of Ma-Lauer with cell-derived vesicles comprising wild-type p53 from the teachings of Tendler, because cell-derived vesicle comprising p53 is more stable than p53 alone, and arrive at applicants claimed invention with a reasonable expectation of success.
Further, advantages of drug delivery systems comprising multilayer lipid vesicles are known in the art. For example, Adrienne teaches a novel and inventive drug delivery systems with higher loading capability, which include compositions including stabilized multilamellar lipid vesicles having crosslinked lipid bilayers covalently conjugated to an agent (e.g., an antigen), wherein antigen can be p53 [see Abstract and 0035]. Irvine also teaches drug delivery systems with higher loading capability, comprise stabilized multilamellar lipid vesicles having crosslinked lipid bilayers, wherein stabilized multilamellar vesicles comprise terminal-cysteine-bearing antigens or cysteine-modified antigens, at their surface and/or internally, wherein antigen can be p53 [see Summary of intention and 0144].
Therefore, a skilled person in the art would be motivated to incorporate p53 with vesicles, since these are proven to be effective in delivering antigens or p53 etc.
For claim 5:
Ma-Lauer teaches SARS-CoV, which is a RNA virus.
For claim 6:
Ma-Lauer silent on viral infection caused by DNA virus. However, the following art teaches nexus between p53 and its antiviral activity on viral infection caused by DNA viruses:
Aloni-Grinstein teaches small DNA viruses, Adenoviruses and SV40, are able to manipulate the host cells by the binding of their viral proteins, E1A and SV40 T-antigen, to the Rb, and this binding releases Rb from E2F, leading to E2F transcriptional activation that mediates S phase entrance. p53 as the “guardian of the genome”, senses this aberrant S phase movement and acts to induce apoptosis, and in another study, eliminating p53 activity, the viral T-antigen or the adenovirus E1B proteins bind p53 and by that inactivate it, allowing the progression into S-phase.
Aloni-Grinstein further teaches that immediately after SV40 infection, activated p53 is noticed only in cells that do not express SV40 viral proteins, suggesting a p53-dependent decision between abortive and productive infection. These p53 host defense mechanisms did not rely on apoptosis, cell cycle arrest, or induction of interferon-stimulated genes, but rather on binding competition between p53 and Sp1, a host protein, which is essential for SV40 assembly. [See abstract, section 2 in pages 2-3 and Table 1].
Further, Lazo teaches that pharmacological rescue of p53 functions might help to control viral infections and teaches effect of p53 on DNA viruses, viz., papoviruses and adenoviruses etc. [see section Interaction of viral proteins with p53 in pages 288-289].
For claim 8:
Ma-Lauer teaches that p53 inhibits replication of SARS-CoV, which is a coronavirus.
For claim 12:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that the cell derived vesicles comprises exosomes [see page 5, lines 5-6].
For claim 13:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches
that cell derived vesicles are essentially devoid of intact cells [see page 5, lines 13-14].
For claims 16, 20 and 21:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that wherein the cells are animal tissue, wherein the animal tissue comprises eye tissues, wherein eye tissue comprises corneal epithelium tissue, wherein corneal epithelium tissue comprises corneal epithelial cells [see page 5, lines 15-20].
For claims 24-25:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that the cells are healthy cells and cells are not genetically non-modified cells [see page 6, lines 1-2].
For claims 28 and 30:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that cells are treated with DNA damaging agent to activate p53 [see page 5, lines 28-30], and wherein DNA damaging agent phosphorylates p53 [see page 11, lines 18-19 and 30-31].
For claim 31:
In addition to the reasoning mentioned under For claim 1 above, Tendler further teaches that wherein outer surface of the cell derived vesicles comprises a heterologous moiety for targeted delivery of the cell derived vesicles to a target cell [see page 5, lines 9-10].
For claim 38:
Ma-Lauer silent on human subject. However, Ma-Lauer established a fact that p53 inhibits viral infection in human cell lines. This can be interpreted as ‘subject is human’. Alternatively, based on the findings from Ma-Lauer, a skilled person in the art can extrapolate teachings of Ma-Lauer to human subject in light of well established delivery technologies.
Based on the above established facts from the cited prior art, it appears that all the claimed elements, i.e, applicants individual components in the claimed method, were known in the prior art, and one skilled person in the art could have combined the elements as claimed by known relationships, with no change in their respective functions, and the combination would have yielded predictable results to one of ordinary skill in the art.
The motivation to combine the art can arise from the expectation that the prior art elements will perform their expected functions to achieve their expected results when combined for their common known purpose. See MPEP 2144.07. Therefore, it would have been obvious to one of ordinary skill in the art before the effective filing date of the claimed invention by taking the advantage of the teaching of the above cited reference and to make the instantly claimed method with a reasonable expectation of success.
The strongest rationale for combining references is a recognition, expressly or impliedly in the prior art or drawn from a convincing line of reasoning based on established scientific principles or legal precedent, that some advantage or expected beneficial result would have been produced by their combination. In re Sernaker, 702 F.2d 989, 994-95, 217 USPQ 1, 5-6 (Fed. Cir. 1983).
II. Claim 3 is rejected under 35 U.S.C. 103 as being unpatentable over Ma-Lauer (PNAS, 2016, Aug 12, E5192-E5201; see applicants filed IDS dated 12/04/2022) in view of Tendler (WO 2018/173059 A1; see applicants filed IDS dated 12/04/2022), Adrienne (US 2017/0246288 A1) and Irvine (US 2018/0360952 A9).
Ma-Lauer teaches a method, wherein p53 inhibits replication of SARS-CoV, wherein the method comprises infecting human ACE2-transgenic p53-expressing HCT116 cells (HCT116/ACE2 p53+/+) as well as p53 knockout cells (HCT116/ACE2 p53−/−) with SARS-CoV, and viral replication was monitored by real-time PCR., SARS-CoV grew to an ∼1,000-fold higher titer in p53−/− cells compared with p53+/+ [see abstract, section P53 Inhibits Replication of a SARS-CoV in pages E5196-E5197 and Fig.6].
Above is interpreted as a method of inducing cell cycle arrest and/or apoptosis of a viral infection.
The difference is that Ma-Lauer is silent on ‘cell-derived vesicles comprising wild-type p53’.
The following art and the reasoning cures the above deficiency:
Tendler teaches cell derived vesicles comprising an active wild-type p53, wherein microvesicles serve as signaling payloads containing cell-specific collections of proteins, lipids and genetic material that are transported to other cells where they can alter cell' s function and physiology. Exosomes, microvesicles of about 40-200 nm in diameter, have pleiotropic biological functions, including immune response, antigen presentation, intracellular communication, and cell to cell transfer of RNA and proteins. Exosomes are typically formed when cellular compartments known as multivesicular endosomes (MVE) or multivesicular bodies (MVB) bud inward to form small internal vesicles containing proteins, mRNAs and miRNA from the cytoplasm. These internal vesicles are released as exosomes when MVE fuse with the cell membrane or, alternatively fuse with lysosomes. Tendler further states that recently, experiments with exosomes as means of chemo- and other therapy delivery vehicles were reported, e.g. as means for delivery of drugs, microRNAs, siRNAs, and antigens to target recipient cells in order to treat tumorigenesis or metastasis [See page 1 and Summary of Invention].
Tendler further teaches that Normal p53 is inactivated by interaction with overexpression of MDM2/MDM4 or viral proteins causing its degradation. High levels of p53 is found in the cytoplasm of corneal epithelium cells, wherein high levels of p53 are accompanied by absence of MDM2. [see page 2].
Therefore, a skilled person in the art would be motivated to replace p53 in the teachings of Ma-Lauer with cell-derived vesicles comprising wild-type p53 from the teachings of Tendler, because cell-derived vesicle comprising p53 is more stable than p53 alone, and arrive at applicants claimed invention with a reasonable expectation of success.
Further, advantages of drug delivery systems comprising multilayer lipid vesicles are known in the art. For example, Adrienne teaches a novel and inventive drug delivery systems with higher loading capability, which include compositions including stabilized multilamellar lipid vesicles having crosslinked lipid bilayers covalently conjugated to an agent (e.g., an antigen), wherein antigen can be p53 [see Abstract and 0035]. Irvine also teaches drug delivery systems with higher loading capability, comprise stabilized multilamellar lipid vesicles having crosslinked lipid bilayers, wherein stabilized multilamellar vesicles comprise terminal-cysteine-bearing antigens or cysteine-modified antigens, at their surface and/or internally, wherein antigen can be p53 [see Summary of intention and 0144].
Therefore, a skilled person in the art would be motivated to incorporate p53 with vesicles, since these are proven to be effective in delivering antigens or p53 etc.
Therefore, a skilled person in the art would be motivated to replace p53 in the teachings of Ma-Lauer with cell-derived vesicles comprising wild-type p63 from the teachings of Tendler or make vesicles comprising p53 in light of their advantages as evidenced from Adrienne and Irvine, and arrive at applicants claimed invention with a reasonable expectation of success.
Conclusion
Any inquiry concerning this communication or earlier communications from the examiner should be directed to SUDHAKAR KATAKAM whose telephone number is (571)272-9929. The examiner can normally be reached 8:30 am to 5 pm.
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SUDHAKAR KATAKAM
Primary Examiner
Art Unit 1658
/SUDHAKAR KATAKAM/Primary Examiner, Art Unit 1658
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