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 .
This application is now under examination by Valarie Bertoglio, AU 1632.
This action is Non-Final.
Election/Restrictions
Applicant’s election without traverse of claims 38-50 in the reply filed on 11/19/24 is acknowledged.
Status of the Claims
The amendment and arguments submitted on 3/20/26 have been entered. Claims 38, 48, 55, and 59-61 have been amended. Claims 45-47 and 56-59 have been cancelled. New claims 62-63 have been added. Claims 51-55 are withdrawn. Claims 38-44, 48-50 and 59-63 are under consideration.
Claim 59 has the claim status indicator “Previously Presented” but should read “Currently Amended”. Claim 55 contains a small deletion that should be indicated with double brackets rather than a strikethrough.
Claim Rejections - 35 USC § 101-Maintained in Modified Form
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 38-44, 46-50 and 59-61 remain rejected and newly added claims 62-63 are rejected under 35 U.S.C. 101 because the claimed invention is directed to a natural phenomenon without significantly more. The claim(s) recite(s) a pharmaceutical composition comprising a therapeutically effective amount of exosomes isolated from endothelial cells and a pharmaceutically acceptable excipient, wherein the exosomes comprise exosomal marker proteins Alix and CD63, and endothelial cell protein CD31, the therapeutically effective amount being sufficient to prevent or treat cancer neurotoxicity or chemotherapy-induced side effects caused by the administration of at least one platinum based chemotherapeutic agent, or treat cancer with a platinum based chemotherapeutic agent.
This judicial exception is not integrated into a practical application because the claims do not require any additional elements that would integrate the exosomes. The claim(s) does/do not include additional elements that are sufficient to amount to significantly more than the judicial exception because the pharmaceutically acceptable excipient is generically recited. Addition of an amount to the claim also fails to add significantly more to the composition and thus the new limitation with regard to what the recited amount is effective to treat, also fails to add significantly more to the judicial exception (the exosomes).
Thus, the broadest reasonable interpretation (BRI) of the claimed invention is a composition comprising exosomes, expressing Alix, CD63 and CD31, isolated from endothelial cells and an excipient.
Step 1: Whether the Claim is to a Statutory Category of Invention
The statutory categories of invention under 35 U.S.C. 101 are processes, machines, manufactures, and compositions of matter. Under Step 1 of the subject matter eligibility test for products and processes, it must be determined if the claims are directed to a process, machine, manufacture or a composition of matter. In the instant case, claim 38 is directed to a composition of matter (a pharmaceutical composition comprising a therapeutically effective amount of exosomes isolated from endothelial cells and a pharmaceutically acceptable excipient).
Step 1: YES
Step 2A: ‘Directed to a judicial exception’ analysis:
Prong One: Does the claim recite an abstract idea, law of nature, or natural phenomenon?
As stated above the BRI of claimed pharmaceutical composition is a composition comprising exosomes expressing Alix, CD63 and CD31, isolated from endothelial cells, which are a natural phenomenon.
Exosomes comprising exosomal marker proteins Alix and CD63, and endothelial cell protein CD31 are known to exist in nature (see the teachings of Haqqani et al. as evidenced by Simpson and Werner below under the 35 USC 102 rejection). Haqqani discloses exosomes comprising common marker proteins Alix and CD63 (see the abstract and table 1 at page 8). Simpson provides evidence that Alix and CD63 are markers present on all exosomes (see Table 4) while Werner discloses that exosomes derived from endothelial cells comprise the endothelial specific marker CD31 (abstract and throughout).
Markedly different characteristics can distinguish from naturally occurring products and can be expressed as the product's structure, function, and/or other properties. Non-limiting examples of characteristics that can determine the presence of a marked difference include biological or pharmacological functions or activities; chemical and physical properties; phenotype, including functional and structural characteristics; and structure and form, whether chemical, genetic, or physical.
However, the claimed exosomes appear to be structurally and functionally the same as those occurring in nature. Moreover, Applicant has not provided evidence of a markedly different characteristic between the claimed composition comprising exosomes isolated from endothelial cells and naturally occurring exosomes isolated from endothelial cells.
Step 2A Prong 1: YES
Prong Two: Does the claim recite additional elements that integrate the judicial exception into a practical application?
Under Step 2A, prong 2 of the analysis, it must be determined whether the claim recites additional elements that integrate the judicial exception into a practical application. In the instant case, while claim 38 recites that the pharmaceutical composition comprises a pharmaceutically acceptable excipient, this limitation does not integrate the exosomes into a practical application because it is a generic limitation that does not affect a particular treatment or prophylaxis or effect a transformation of the exosomes to a different state. See MPEP 2106.04(d). It is noted that the claims also recite, “the therapeutically effective amount being sufficient to prevent or treat cancer neurotoxicity or chemotherapy-induced side effects caused by the administration of at least one platinum based chemotherapeutic agent, or treat cancer with a platinum based chemotherapeutic agent”. This is the equivalent of an intended use or capable of language which fails to integrate the exosomes into a practical application. Further, the chemotherapeutic agent does not appear to be claimed embodiment but rather a conditional claim element or descriptor of an amount.
Thus, the claim as whole is not integrated into a practical application.
Step 2A Prong 2: NO
Step 2B: ‘Significantly More’ Analysis
Claim 38 recites a pharmaceutically acceptable excipient in addition to the exosomes. However, the excipient is recited generically and is considered to be well-understood, routine and conventional not adding significantly more to the claim. As stated above, “the therapeutically effective amount being sufficient to prevent or treat cancer neurotoxicity or chemotherapy-induced side effects caused by the administration of at least one platinum based chemotherapeutic agent, or treat cancer with a platinum based chemotherapeutic agent, is considered intended use, descriptive or capable of language which fails to add significantly more to the claims. Further, the chemotherapeutic agent does not appear to be claimed embodiment but rather a conditional claim element and also fails to add significantly more.
Step 2B: No
Accordingly, the claims are directed to a judicial exception and not patent eligible.
Response to Arguments
Applicant argues that the claim 59 has been amended to require exosomes isolated from a supernatant of cerebral endothelial cells that is filtered by size and includes on or more media proteins. This argument is not persuasive because not only are culturing in a media and inclusion of the additional additives (media proteins) into the composition comprising the exosome recited with a high level of generality, the presence of the media proteins is not supported to alter the claimed exosomes in any way. Reciting exosomes and a one or more prtoeins from culture media with a high level of generality fails to alter the exosomes and fails to add significantly more to the judicial exception.
A claim to an inoculant comprising a plurality of strains of different bacterial species whereby the strains are unaffected by each other was found to not add significantly more to the judicial exception of a nature-based product. The inoculant of claim 1 was held to be ineligible subject matter in Funk Brothers Seed Co. v. Kalo Inoculant Co., 333 U.S. 127, 131 (1948):
Discovery of the fact that certain strains of each species of these bacteria can be mixed without harmful effect to the properties of either is a discovery of their qualities of non-inhibition. It is no more than the discovery of some of the handiwork of nature and hence is not patentable. The aggregation of select strains of the several species into one product is an application of that newly-discovered natural principle. But however ingenious the discovery of that natural principle may have been, the application of it is hardly more than an advance in the packaging of the inoculants. Each of the species of root-nodule bacteria contained in the package infects the same group of leguminous plants which it always infected. No species acquires a different use. The combination of species produces no new bacteria, no change in the six species of bacteria, and no enlargement of the range of their utility. Each species has the same effect it always had. The bacteria perform in their natural way. Their use in combination does not improve in any way their natural functioning. They serve the ends nature originally provided and act quite independently of any effort of the patentee.
The Supreme Court looked back to this claim as an example of ineligible subject matter, stating that “the composition was not patent eligible because the patent holder did not alter the bacteria in any way.” Myriad, 133 S. Ct. at 2117.
Applicant argues that the therapeutically effective amount is not an intended use but a meaningful claim limitation that indicates the concentration of the claimed composition of exosomes. This argument is not persuasive. While it is agreed that this language is descriptive of the amount or concentration, this fails to change or transform the exosomes such that the differ from those in nature. It is concluded, here, that the claimed natural products are not markedly different from their natural counterparts as a result of a formulating them into a particular concentration or amount.
Applicant asserts the claimed pharmaceutically acceptable excipient anf therapeutically effective amount are recitations that add significantly more. In response, it is not clear from the claim what markedly different characteristics of the claimed exosomes or additional claim elements would “prevent or treat cancer neurotoxicity or chemotherapy-induced side effects”; the claimed exosomes appear to be merely isolated from cells and not modified in any way given the teachings of the specification. If this is intended to be a property of the claimed exosome composition it would be helpful if applicant could point to differences in the exosome structure resulting in the ability to prevent or treat cancer neurotoxicity or chemotherapy-induced side effects. As noted above, chemotherapeutic agent as recited is not part of the claimed composition of exosomes.
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.
The previous rejection of claim(s) 38-39, 41-44, 46-48, 50, 59, 60 and 61 under 35 U.S.C. 102(a)(1) as being anticipated by Haqqani (of record) as evidenced by Simpson et al (Proteomics, 8, 2008, pages 4083-4099) and Werner et al (Arteriosclerosis, Thrombosis, and Vascular Biology, Vol 1, Issue 1, 1 January 2006, pages 112-116) is withdrawn in favor of the following new rejection that replaces Werner with Burtenshaw to support the presence of CD31 in endothelial exosomes.
Claim(s) 38-39, 41-44, 46-48, 50, 59, and 60-63 is/are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Haqqani (Fluids and Barriers of the CNS 2013, 10:4, of record) as evidenced by Simpson et al (Proteomics, 8, 2008, pages 4083-4099, of record) and Burtenshaw (2022, Frontiers in Cell and Developmental Biology, 10:853451, 22 pages, newly cited).
Regarding claim 38, Haqqani discloses exosomes isolated from human brain endothelial cells (HBECs, cerebral endothelial cells, claim 62 and 63), wherein the exosomes express markers including Alix and CD63 (abstract; Table 1 at pg. 8). Haqqani goes on to discuss that Alix and CD63 are known markers of exosomes as evidenced by Simpson. See page 5, column 2 and Table 1-which shows overlap of known exosomal markers and those identified by Haqqani in HBEC-EMVs (and cites Simpson). The Simpson reference, as cited by Haqqani in support of known exosomal markers, provides a list of proteins commonly found in all exosomes studied to date (see Table 1, at page 4093), wherein the list cites Alix and CD63. Therefore, Alix and CD63 are known exosomal markers found in all exosomes including exosomes in HBEC-EMVs. Haqqani does not explicitly teach that endothelial exosomes would comprise endothelial cell protein CD31. However, it was known in the art exosomes derived from endothelial cells comprise the endothelial marker, CD31 as evidenced by Burtenshaw. Burtenshaw states, “…vascular ECs retain the ability to release exosomes into the extracellular space in response to cellular activation or apoptosis…. They are characterized by expression of various EC specific surface markers (CD31, CD55, CD144 and von Willebrand factor).” (page 8, col. 1).
Regarding claims 39 and 41, the cells are specifically human (claim 41) brain microvascular endothelial cells (HBEC, BMVECs as claimed, claim 39) (Methods par. 1 in pg. 2). Additionally, claim 38 is interpreted as not requiring a chemotherapeutic agent as the treatment of cancer is recited as an intended use of the pharmaceutical composition. Accordingly, claim 48 is anticipated by Haqqani evidenced by Burtenshaw and included in the instant rejection.
Regarding claim 42, Haqqani teaches autologous exosomes (pg. 11, left col., par. 2). With respect to claim 43, the human cells are cultured cells (Methods par. 1 in pg. 2).
Regarding claims 44 and 50, Haqqani does not disclose that the exosomes target DRG neurons and sciatic nerve tissue (claim 44) or that the composition is effective in preventing or treating neurotoxicity in a subject (claim 50). However, since the exosomes taught by Haqqani are the same as the claimed exosomes, such properties would be considered inherent properties of the exosomes.
Regarding claim 59, as discussed above Haqqani as evidenced by Burtenshaw teach the structural features of the claimed exosomes, namely that they comprise Alix, CD63 and CD31. “Isolated from supernatant and supernatant is filtered by size” are product by process limitations that do not appear to change the structure of the exosomes and are given little weight for the purposes of the instant prior art rejection.
Regarding claims 60-61, as discussed above Haqqani as evidenced by Simpson and Burtenshaw, teach the structural features of the claimed exosomes, namely that they comprise Alix, CD63 and CD31. “Isolated from endothelial cells…wherein the endothelial cells have been treated with a chemotherapy agent” is a product by process limitation that does not appear to structurally change the exosomes and is given little weight for the purposes of the instant prior art rejection. Applicant is encouraged to reply wit evidence that treating the endothelial source cells with an alkylating chemotherapeutic agent will result in exosomes that differ in characteristics.
Thus, the claims are anticipated by Haqqani as evidenced by Simpson and Burtenshaw.
Applicant’s arguments to the withdrawn rejection are addressed below as they may relate to the new rejection.
Applicant argues that while secondary references may be used to show that a characteristic is inherent, it must make clear that the missing descriptive matter is necessarily present. It is maintained that the evidentiary references do this. It is established by these references that Alix and CD63 are present in all exosomes and CD31 are present in some (i.e CD31 is present in endothelial cell secreted exosomes). Thus, exosomes from HBECs (human brain/cerebral endothelial cells) would express endothelial-specific CD31 in combination with exosome markers Alix and CD63.
Applicant argues that Haqqani fails to disclose exosomes comprising Alix, CD63 and CD31 at the same time. In response, if all exosomes comprise Alix and CD63 and some exosomes contain CD31, then some exosomes comprise all 3.
Applicant argues that Werner (previous rejection; withdrawn) does not use the word “exosome” but refers to endothelial microparticles and apoptotic microparticles. While it is not necessarily agreed that the particles (apoptotic microparticles) of Werner don’t comprise CD31, to the extent that exosomes and apoptotic microparticles are distinct and are different sizes and contain different cellular proteins, the Werner reference was replaced with the Burtenshaw reference.
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 rejection of claim(s) 38, 40 and 49 under 35 U.S.C. 103 as being unpatentable over Haqqani as evidenced Werner in view of Zhuang et al (Molecular Therapy, October 2011, Vol 19, No 10, pages 1769-1779) is withdrawn (see the withdrawal of the rejection under 35 USC 102, above).
Claim(s) 38, 40 and 49 is/are rejected under 35 U.S.C. 103 as being unpatentable over Haqqani as evidenced by Simpson and Burtenshaw in view of Zhuang et al (Molecular Therapy, October 2011, Vol 19, No 10, pages 1769-1779).
The above teachings of Haqqani as evidenced Burtenshaw above are relied on with regard to claim 38.
The teachings of Haqqani as evidenced Burtenshaw do not teach a pharmaceutical composition comprising exosomes in an amount ranging from 1 x 101 to 1 x 1015 exosomes per ml. However, at the time the invention was effectively filed pharmaceutical compositions comprising exosomes in an amount ranging from 1 x 101 to 1 x 1015 exosomes per ml were contemplated the art as provided by Zhang.
Regarding claim 40, Zhang teaches intranasal delivery, into mice, of a pharmaceutical composition of exosomes at concentration of 2 mg/ml (see page 1777, 3rd full paragraph). While Zhang does not teach the concentration range of exosomes recited in claim 40, that concentration range would be within the realm of routine experimentation. Generally, differences in concentration or temperature will not support the patentability of subject matter encompassed by the prior art unless there is evidence indicating such concentration or temperature is critical. "[W]here the general conditions of a claim are disclosed in the prior art, it is not inventive to discover the optimum or workable ranges by routine experimentation." In re Aller, 220 F.2d 454, 456, 105 USPQ 233, 235 (CCPA 1955). See MPEP § 2144.05 part II A.
Regarding claim 49, Haqqani suggests the exosomes may be formulated for intranasal delivery (page 11, left col, paragraph 3) and cites the work of Zhang. Zhang teaches intranasal delivery of a pharmaceutical compositions comprising exosomes to mice (see page 1777, 3rd full paragraph and throughout the reference).
Accordingly, it would be obvious to one of ordinary skill in the art at the effective filing date of the invention to optimize the concentration of exosomes in a pharmaceutical composition as taught by Haqqani evidenced by Werner and Zhang. A person of ordinary skill would have been motivated to optimize the concentration of exosomes in order to optimize for intranasal delivery as taught by Zhang.
Therefore, the invention as a whole was prima facie obvious to one of ordinary skill at the effective filing date of the invention in the absence of evidence to the contrary.
Double Patenting
The rejection of claims 38-42, 44, 46-50, and 59-61 on the ground of nonstatutory double patenting as being unpatentable over claims 1, 6-7, 10, 12-13, 14, 34 and 39 of U.S. Patent No. 11,357,800 in view of Haqqani evidenced by Simpson and Werner is withdrawn in view of the Terminal Disclaimer filed 03/20/2026.
Conclusion
No claim is allowed.
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VALARIE E. BERTOGLIO, Ph.D.
Examiner
Art Unit 1632
/VALARIE E BERTOGLIO/Primary Examiner, Art Unit 1632
/PETER PARAS JR/Supervisory Patent Examiner, Art Unit 1632
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