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and the fee set forth in 37 CFR 1.17(e) has been timely paid, the finality of the previous Office action has been withdrawn pursuant to 37 CFR 1.114.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 April 14, 2026 has been entered.
Detailed Action
This action is in response to the papers filed April 14, 2026.
Amendments
Applicant's response and amendments, filed April 14, 2026, to the prior Office Action are acknowledged.
Applicant has cancelled Claims 2, 9, and 14-17, amended Claims 1, 5, 11, and 13, and withdrawn Claims 5-8, and 10-13.
Claims 1, 3-8, and 10-13 are pending.
Election/Restriction
Applicant's election without traverse of Group I, claims 1-4, directed to an extracellular vesicle comprising an exogenous therapeutic component, in Applicants’ response filed on March 22, 2024 is acknowledged.
Claims 1, 3-8, and 10-13 are pending.
Claims 5-8 and 10-13 are withdrawn from further consideration by the Examiner, pursuant to 37 CFR 1.142(b), as being drawn to non-elected inventions, there being no allowable generic or linking claim. Claims that were drawn to a non-elected invention would have been withdrawn, as being directed to a non-elected invention. Reinstatement of claims drawn to non-elected inventions will be withdrawn during prosecution.
Claims 1 and 3-4 are under examination.
Priority
The present application is a 35 U.S.C. 371 national stage filing of International Application No. PCT/US2019/043172, filed July 24, 2019. Applicants’ claim for the benefit of prior-filed parent provisional application 62/702,882 filed on July 24, 2018 is acknowledged.
The later-filed application must be an application for a patent for an invention which is also disclosed in the prior application (the parent or original nonprovisional application or provisional application). The disclosure of the invention in the parent application and in the later-filed application must be sufficient to comply with the requirements of 35 U.S.C. 112(a) or the first paragraph of pre-AIA 35 U.S.C. 112, except for the best mode requirement. See Transco Products, Inc. v. Performance Contracting, Inc., 38 F.3d 551, 32 USPQ2d 1077 (Fed. Cir. 1994)
The disclosure of the prior-filed applications, 62/702,882 filed on July 24, 2018 and PCT/US2019/043172, filed July 24, 2019, fail to provide adequate support or enablement in the manner provided by 35 U.S.C. 112(a) or pre-AIA 35 U.S.C. 112, first paragraph for one or more claims of this application.
Applicant has amended the independent Claim 1 to recite product-by-process steps of:
i) isolating exosomes from a biological starting material [structure 1];
ii) lyophilizing the exosomes in the presence of protein [structure 2] from the [structure 1] starting material from which the exosomes are prepared, the [structure 2] protein providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1]; and
iii) reconstituting the lyophilized exosomes in a liquid comprising a detergent.
Applicant argues that support for these limitations are found in the instant specification, pg 11, lines 4-7.
The specification Example 1 refers back to WO 19/118817 (e.g. pg 11, “exosomes prepared as previously described in WO 19/118817”).
While WO 19/118817 discloses contemplation that the purified exosome product (PEP) may have a shelf-life of at least six months to as long as four years without refrigeration (e.g. pg 14, lines 2-3), such disclosure(s) is devoid of the nexus of:
i) instantly recited biological starting material [structure 1], recited at a high level of generality;
ii) instantly recited protein [structure 2], recited at a high level of generality, from the [structure 1] starting material from which the exosomes are prepared; and
iii) the correspond working concentration(s) [method step parameter 1] of said protein [structure 2], recited at a high level of generality,
in order to achieve the instantly recited result of providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1].
Instant specification is silent to “four” and “refrigeration”.
With respect to the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent, a keyword search for “detergent” fails to identify the term, or synonym thereof, in the WO 19/118817 disclosure. Example 1 also fails to disclose the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent.
While instant specification discloses “detergent” (e.g. pg 9, line 29), such is in the context of method steps by which the therapeutic agent may be loaded into the exosomes, not the instantly recited step of reconstituting lyophilized exosomes.
See further discussion in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description New Matter rejection below.
Accordingly, the effective priority date of the instant application is granted as January 20, 2021, the filing date of the instant application.
If applicant believes the earlier applications provide support for this disclosure, applicant should point out such support with particularity by page and line number in the reply to this Action.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on April 14, 2026 that has been considered.
The signed and initialed PTO Forms 1449 are mailed with this action.
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.
1. The prior rejection of Claims 14-17 under 35 U.S.C. 112(d) or pre-AIA 35 U.S.C. 112, 4th paragraph, is withdrawn in light of Applicant’s cancellation of the claims.
2. The prior rejection of Claims 15-16 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s cancellation of the claims.
3. The prior rejection(s) of Claims 1, 3-4, and 14-17 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to Claim 1 to recite the exosomes comprise a heterologous therapeutic agent, which the Examiner finds persuasive.
4. The prior rejection of Claims 1, 3-4, and 14-17 under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, is withdrawn in light of Applicant’s amendment to Claim 1 to recite the product-by-process steps of the exosomes prior to introducing the heterologous therapeutic agent into said exosomes, which the Examiner finds persuasive.
New Matter
5. Claims 1 and 3-4 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.
Applicant has amended the independent Claim 1 to recite product-by-process steps of:
i) isolating exosomes from a biological starting material [structure 1];
ii) lyophilizing the exosomes in the presence of protein [structure 2] from the [structure 1] starting material from which the exosomes are prepared, the [structure 2] protein providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1]; and
iii) reconstituting the lyophilized exosomes in a liquid comprising a detergent.
Clear support for the new limitation(s) (underlined) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim 1 is/are considered to constitute new matter.
MPEP 2163.06 notes “If new matter is added to the claims, the examiner should reject the claims under 35 U.S.C. 112, first paragraph - written description requirement. In re Rasmussen, 650 F.2d 1212, 211 USPQ 323 (CCPA 1981).” MPEP 2163.02 teaches that “Whenever the issue arises, the fundamental factual inquiry is whether a claim defines an invention that is clearly conveyed to those skilled in the art at the time the application was filed...If a claim is amended to include subject matter, limitations, or terminology not present in the application as filed, involving a departure from, addition to, or deletion from the disclosure of the application as filed, the examiner should conclude that the claimed subject matter is not described in that application”. MPEP 2163.06 further notes “When an amendment is filed in reply to an objection or rejection based on 35 U.S.C. 112, first paragraph, a study of the entire application is often necessary to determine whether or not “new matter” is involved. Applicant should therefore specifically point out the support for any amendments made to the disclosure” (emphasis added).
Applicant argues that support for these limitations are found in the instant specification, pg 11, lines 4-7.
The specification Example 1 refers back to WO 19/118817 (e.g. pg 11, “exosomes prepared as previously described in WO 19/118817”).
While WO 19/118817 discloses contemplation that the purified exosome product (PEP) may have a shelf-life of at least six months to as long as four years without refrigeration (e.g. pg 14, lines 2-3), such disclosure(s) is devoid of the nexus of:
i) instantly recited biological starting material [structure 1], recited at a high level of generality;
ii) instantly recited protein [structure 2], recited at a high level of generality, from the [structure 1] starting material from which the exosomes are prepared; and
iii) the correspond working concentration(s) [method step parameter 1] of said protein [structure 2], recited at a high level of generality,
in order to achieve the instantly recited result of providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1].
Instant specification is silent to “four” and “refrigeration”.
With respect to the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent, a keyword search for “detergent” fails to identify the term, or synonym thereof, in the WO 19/118817 disclosure. Example 1 also fails to disclose the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent.
While instant specification discloses “detergent” (e.g. pg 9, line 29), such is in the context of method steps by which the therapeutic agent may be loaded into the exosomes, not the instantly recited step of reconstituting lyophilized exosomes.
See further discussion in the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description New Matter rejection below.
Alternatively, if Applicant believes that support for instantly recited limitations is/are present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, point out such support with particularity by page and line number in the reply to this Office Action.
Applicant does not indicate where these limitations are supported by the original specification, or how, as is Applicant's burden. See MPEP §714.02, last sentence of the third paragraph from the end and MPEP §2163.06 (I) last sentence.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
6. Claims 1 and 3-4 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.
Applicant has amended the independent Claim 1 to recite product-by-process steps of:
i) isolating exosomes from a biological starting material [structure 1];
ii) lyophilizing the exosomes in the presence of protein [structure 2] from the [structure 1] starting material from which the exosomes are prepared, the [structure 2] protein providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1]; and
iii) reconstituting the lyophilized exosomes in a liquid comprising a detergent.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, New Matter rejection.
The claim suffers from a gap in the structure(s) and method step(s)/functional property nexus for failing to recite the protein [structure 2], recited at a high level of generality, the correspond working concentration(s) [method step parameter 1] of said protein [structure 2], recited at a high level of generality, and the corresponding biological starting material [structure 1] comprising said protein [structure 2] that necessarily and predictably achieves the functional property/method result of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1].
The claim denotes that not all proteins [structure 2], recited at a high level of generality, and/or not all the concentration(s) [method step parameter 1] of said proteins [structure 2], recited at a high level of generality, have the functional property/method result of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1].
Thus, the claim(s) suffer from a lack of adequate written description because there is:
a first protein [structure 2] subgenus and/or a first protein concentration [method step parameter 1] that does not achieve the functional property/method result of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], as opposed to
a second protein [structure 2] subgenus and/or a second protein concentration [method step parameter 1] that does necessarily and predictably achieve(s) the functional property/method result of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1].
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In analyzing whether the written description requirement is met for genus claims, it is first determined whether a representative number of species have been described by their complete structure. 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 complete or partial structure, physical and/or chemical properties, functional characteristics, structure/function correlation, methods of making the claimed product, or any combination thereof. The disclosure of a single species is rarely, if ever, sufficient to describe a broad genus, particularly when the specification fails to describe the features of that genus, even in passing. (see In re Shokal 113USPQ283(CCPA1957); Purdue Pharma L.P. vs Faulding Inc. 56 USPQ2nd 1481 (CAFC 2000).
The court explained that “reading a claim in light of the specification, to thereby interpret limitations explicitly recited in the claim, is a quite different thing from ‘reading limitations of the specification into a claim,’ to thereby narrow the scope of the claim by implicitly adding disclosed limitations which have no express basis in the claim.” The court found that applicant was advocating the latter, i.e., the impermissible importation of subject matter from the specification into the claim.). See also In re Morris, 127 F.3d 1048, 1054-55, 44 USPQ2d 1023, 1027-28 (Fed. Cir. 1997).
The claimed biological starting material [structure 1] is recited at a high level of generality, and encompasses both cell cultured in vitro or biological samples isolated from a subject.
The prior art recognizes exosomes are naturally produced by animals such as the nematode worm, Caenorhabditis elegans (e.g. Liegeois et al (The V0-ATPase mediates apical secretion of exosomes containing Hedgehog-related proteins in Caenorhabditis elegans, J. Cell Biol. 173(6): 949-961, 2006)).
The prior art recognizes exosomes are naturally produced by plants (e.g. Hansen et al (Plant exosomes: using an unconventional exit to prevent pathogen entry?, J. Exp. Botany 69(1): 59-68, doi.org/10.1093/jxb/erx319; available online September 19, 2017).
The prior art recognizes exosomes are naturally produced by fungi (e.g. Panepinto et al (Sec6-dependent sorting of fungal extracellular exosomes and laccase of Cryptococcus neoformans, Molecular Microbiology 71(5): 1165-1176, 2009).
The prior art recognizes exosomes are naturally produced by protists (e.g. Clayton et al (THE EXOSOMES OF TRYPANOSOMES AND OTHER PROTISTS, RNA Exosomes, Chapter 4, Torben Heick Jensen, editor, Lanes Bioscience and Spring Scient and Business Media, 2010).
Thus, the breadth of the claimed genus of biological starting material [structure 1] reasonably encompasses about 8.7 million species of eukaryotic organisms, including about 250,000 species of eukaryotic protists, about 100,000 species of fungi, about 250,000 species of plants, and about 1,000,000 species of animals (The Five Kingdoms of Life; waynesword.palomar.edu/trfeb98.htm, last visited April 8, 2021), wherein the mammalian sub-genus reasonably encompasses some 6,400 species (including humans), distributed in about 1,200 genera, about 152 families and about 29 orders (Mammal, en.wikipedia.org/wiki/Mammal, last visited August 31, 2022).
The breadth of the claimed genus of biological starting material also encompasses an essentially infinite genus of cell culture media formulations in which the above enormously vast genus of about 8.7x10^6 different species of eukaryotes may be cultured, whereby those of ordinary skill in the art have long-recognized that culture medium formularies vary tremendously, depending upon the needs of the target cultured cells and the artisan, e.g. Complex media, Selective media, Differential media, Enriched media, or Minimal media.
The claimed protein [structure 2] is recited at a high level of generality.
DiCorato (Broad Institute, Genomes from 240 mammalian species reveal what makes the human genome unique, www.brodinstitute.org/news/zoonomia; last accessed April 27, 2023) taught that only 240 mammalian species have had their genomes sequenced.
The claims are directed to an enormously vast genus of structurally undisclosed proteins encoded by the enormously vast genus of about 8.7x10^6 different species of eukaryotes, whereby Medline Plus (What is a gene?; medlineplus.gov/genetics/understanding/basics/gene; last visited March 4, 2024) teach that, for example, the number of genes in the human genome is between 20,000 and 25,000 genes. It is axiomatic that if the enormously vast genus of about 8.7x10^6 different species of eukaryotes, each of which whose genomes comprise about 20,000 different genes, respectively, have not yet had their genomes sequenced, then one simply does not know the structure/function nexus of the thus-encoded proteins in each of the enormously vast genus of structurally undisclosed proteins encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that will necessarily and predictably achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1].
The breadth of the protein concentration [method step parameter 1] recited in the Claim 1 product-by-process is recited at a high level of generality, whereby the protein is present in a very low amount, essentially little to close-to-none, as there is no lower limit, or may be present in a very high amount, e.g. 10mM, 100mM, 1M, 5M, 10M, etc…, as there is no upper limit.
The claim fails to recite, and the specification fails to disclose, the working concentration [method step parameter 1] of a first protein [structure 2] of the enormously vast genus of structurally undisclosed proteins encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that cannot achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], as opposed to the working concentration [method step parameter 1] of said first protein [structure 2] of the enormously vast genus of structurally undisclosed proteins encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that will necessarily and predictably achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], for example.
The claim fails to recite, and the specification fails to disclose, the working concentration [method step parameter 1] of a first protein [structure 2] of the enormously vast genus of structurally undisclosed proteins encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that cannot achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], as opposed to the working concentration [method step parameter 1] of a second protein [structure 2] of the enormously vast genus of structurally undisclosed proteins encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that will necessarily and predictably achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], for example.
Essentially, Applicant is requiring the ordinary artisan to discover and invent for themselves that which Applicant simply does not possess, nor has disclosed.
Applicant argues that support for these limitations are found in the instant specification, pg 11, lines 4-7.
The specification Example 1 refers back to WO 19/118817 (e.g. pg 11, “exosomes prepared as previously described in WO 19/118817”).
United States Court of Appeals for the Federal Circuit, Regents of the University of Minnesota v. Gilead Sciences, Inc (Case 21-2168; decided March 6, 2023).
Written description of a broad genus requires description not only of the outer limits of the genus but also of either a representative number of members of the genus or structural features common to the members of the genus, in either case with enough precision that a relevant artisan can visualize or recognize the members of the genus. See Ariad Pharms., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1350−52 (Fed. Cir. 2010) (en banc). A broad outline of a genus’s perimeter is insufficient. See id.
Original disclosure may not be relied upon unless it “constitute[s] a full, clear, concise and exact description” of the invention claimed in the patent to one of ordinary skill. In re Wertheim, 646 F.2d 527, 538–39 (CCPA 1981).
For genus claims, which are present here, we have looked for blaze marks within the disclosure that guide attention to the claimed species or subgenus. In re Ruschig, 379 F.2d 990, 994–95 (CCPA 1967); Fujikawa v. Wattana-sin, 93 F.3d 1559, 1571 (Fed. Cir. 1996); see also Purdue Pharma L.P. v. Faulding Inc., 230 F.3d 1320, 1326–27 (Fed. Cir. 2000).
Following this maze-like path, each step providing multiple alternative paths, is not a written description of what might have been described if each of the optional steps had been set forth as the only option. This argument calls to mind what Yogi Berra, the Yankee catcher, was reported to have said: “when one comes to a fork in the road, take it.” That comment was notable because of its indeterminacy, its lack of direction. Similarly, here, all those optional choices do not define the intended result of the instant combination of specific method step parameters.
Clearly, however, just because a moiety is listed as one possible choice for one position does not mean there is ipsis verbis support for every species or sub-genus that chooses that moiety. Were this the case, a “laundry list” disclosure of every possible moiety for every possible position would constitute a written description of every species in the genus. This cannot be because such a disclosure would not “reasonably lead” those skilled in the art to any particular species.
Indeed, the listings of possibilities are so long, and so interwoven, that it is quite unclear how many compounds actually fall within the described genera and subgenera.
As explained by the Board, “[t]hese blaze marks must be clear because ‘it is easy to bypass a tree in the forest, even one that lies close to the trail.’” Decision at *10 (citing Fujikawa, 93 F.3d at 1571).
The Board concluded that, “[i]n this case, we find the point at which one must leave the trail to find the tree is not well marked in [WO 19/118817]. Thus, [WO 19/118817] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
However, WO 19/118817 discloses “reconstituted” in the context of different exosome preparations, for example:
i) simply formulating the exosomes with a pharmaceutically acceptable carrier (e.g. pg 12, lines 5-6);
ii) solubilizing an exosome product (e.g. pg 14, line 6);
iii) solubilizing a dried exosome product (e.g. pg 14, line 7);
iv) exosomes sorted via affinity separation, magnetic bead separation or flow separation based on the presence or absence of a surface marker (pg 19, lines 21-22);
v) exosomes isolated using ultracentrifugation and/or tangential flow filtration (e.g. pg 21, lines 1-2); and
vi) the exosome product is modified to comprise one or more of a genus of structurally different ingredients, e.g. collagen, thrombin, gelatin, alginate, hyaluronic acid (e.g. pg 13, lines 26-29), or PLGA (e.g. pg 14, line 18).
Example 1 of instant application fails to disclose with particularity and specificity the referenced exosome composition of WO 19/118817 that is being reconstituted with sterile water and heparin sulfate in the instant specification.
The claimed “lyophilized composition is recited at a high level of generality, and encompasses an enormous genus of structurally different exosome compositions, per WO 19/118817, including:
i) simply formulating the exosomes with a pharmaceutically acceptable carrier (e.g. pg 12, lines 5-6);
ii) solubilizing an exosome product (e.g. pg 14, line 6);
iii) solubilizing a dried exosome product (e.g. pg 14, line 7);
iv) exosomes sorted via affinity separation, magnetic bead separation or flow separation based on the presence or absence of a surface marker (pg 19, lines 21-22);
v) exosomes isolated using ultracentrifugation and/or tangential flow filtration (e.g. pg 21, lines 1-2); and
vi) the exosome product is modified to comprise one or more of a genus of structurally different ingredients, e.g. collagen, thrombin, gelatin, alginate, hyaluronic acid (e.g. pg 13, lines 26-29), or PLGA (e.g. pg 14, line 18).
WO 19/118817 discloses an enormously broad genus of process step temperatures [parameter 1], freezing rate steps [parameter 2], and vacuum pressures [parameter 3] by which to generate a lyophilized product (e.g. pg 8, line 10-pg 9, line 24), whereby the process may further comprise additional drying steps [parameter 4] and/or terminal temperature changes [parameter 5] (e.g. pg 9, lines 25-pg 10, line 21).
Instant claims fail to recite, and the specifications of instant application and WO 19/118817 fail to disclose, the nexus between the process step(s) parameters 1, 2, 3, 4, and 5 above, individually and/or in combinations and/or subcombinations thereof, that necessarily and predictably achieve the recited functional property of “the lyophilized composition has a shelf life of up to four years without refrigeration” , for example.
While WO 19/118817 does disclose “the purified exosome product has a shelf life of at least six months but as long as four years without refrigeration” (e.g. pg 14, lines 2-3), such is devoid of the process steps that is/are necessary and sufficient to achieve the functional properties.
The disclosure of WO 19/118817 fails to provide ipsis verbis support nor sufficient blaze marks to guide the skilled artisan to the instant claims.
WO 19/118817 discloses an enormously broad genus of structurally distinct biological starting materials from which the exosomes are isolated, including, but not limited to, blood, blood products, umbilical cord Wharton’s jelly, stromal vascular fraction of fat, apheresis bone marrow products, synovial fluid, cerebrospinal fluid, placenta, mesenchymal stem cells, endothelial cells, neural stem cells, embryonic stem cells, induced pluripotent stem cells, or the conditioned medium of these cells or any other cell sources (e.g. pg 2, lines 6-11; pg 7, lines 19-23).
Instant specification discloses an enormously broad genus of structurally distinct biological starting materials from which the exosomes are isolated, including, but not limited to, mesenchymal stem cells, dendritic cells, cardiomyocytes, vascular smooth muscle cells, endothelial cells, fibroblasts, leukocytes (e.g. pg 3, lines 20-24).
Those of ordinary skill in the art would immediately recognize that fat cells and/or tissue comprises a structurally different protein composition profile than cerebrospinal fluid and/or synovial fluid, for example.
Those of ordinary skill in the art would immediately recognize that culture medium for induced pluripotent stem cells is a structurally different formulary than culture medium for fibroblasts or keratinocytes, for example.
Thus, the ordinary artisan would also immediately recognize that the resulting conditioned medium from said iPS cells would yield a structurally different protein composition profile than conditioned medium from fibroblasts or keratinocytes, for example.
At best, WO 19/118817 discloses the biological starting material is a filtered and processed apheretic blood product (e.g. pg 23, Example 1).
However, there is no disclosure of the protein composition and/or concentration thereof of said filtered and processed apheretic blood product from which the exosomes are isolated and then lyophilized.
At best, instant specification (e.g. pg 11, Example 1) refers back to the exosome preparation previously described in the disclosure of WO 19/118817 (e.g. pg 23, Example 1).
Thus, instant specification fails to make up for the deficiencies of WO 19/118817.
While WO 19/118817 discloses contemplation that the purified exosome product (PEP) may have a shelf-life of at least six months to as long as four years without refrigeration (e.g. pg 14, lines 2-3), such disclosure(s) is devoid of the nexus of:
i) instantly recited biological starting material [structure 1], recited at a high level of generality;
ii) instantly recited protein [structure 2], recited at a high level of generality, from the [structure 1] starting material from which the exosomes are prepared; and
iii) the correspond working concentration(s) [method step parameter 1] of said protein [structure 2], recited at a high level of generality,
in order to achieve the instantly recited result of providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1].
Essentially, Applicant is requiring the ordinary artisan to discover and invent for themselves that which Applicant does not disclose.
Instant specification is silent to “four” and “refrigeration”.
While instant specification discloses that “one can freeze dry or lyophilize the transformed product to increase the shelf-life of the transformed product” (e.g. pg 10, lines 2-3), such disclosure is devoid of the nexus of:
i) instantly recited biological starting material [structure 1], recited at a high level of generality;
ii) instantly recited protein [structure 2], recited at a high level of generality, from the [structure 1] starting material from which the exosomes are prepared; and
iii) the correspond working concentration(s) [method step parameter 1] of said protein [structure 2], recited at a high level of generality,
in order to achieve the instantly recited result of providing the lyophilized exosomes with a shelf life of up to four years without refrigeration [function 1].
Essentially, Applicant is requiring the ordinary artisan to discover and invent for themselves that which Applicant does not disclose.
Here too, instant specification fails to make up for the deficiencies of WO 19/118817.
With respect to the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent, a keyword search for “detergent” fails to identify the term, or synonym thereof, in the WO 19/118817 disclosure. Example 1 also fails to disclose the instantly recited process step of reconstituting the lyophilized exosomes in a liquid comprising a detergent.
While instant specification discloses “detergent” (e.g. pg 9, line 29), such is in the context of method steps by which the therapeutic agent may be loaded into the exosomes, not the instantly recited step of reconstituting lyophilized exosomes.
Without a correlation between structure and function, the claim does little more than define the claimed invention by function. That is not sufficient to satisfy the written description requirement. See Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406 (“definition by function ... does not suffice to define the genus because it is only an indication of what the gene does, rather than what it is’).
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial protein [structure 2] is to confer the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of structurally undisclosed proteins [structure 2] encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that will necessarily and predictably achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], encompassed by the claims.
What is the genus and/or subgenus of protist proteins, and their corresponding working concentrations, that necessarily and predictably achieves the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, as opposed to the genus and/or subgenus of protist proteins, and their corresponding working concentrations, that do not necessarily and predictably achieve the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes??
What is the genus and/or subgenus of fungal proteins, and their corresponding working concentrations, that necessarily and predictably achieves the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, as opposed to the genus and/or subgenus of fungal proteins, and their corresponding working concentrations, that do not necessarily and predictably achieve the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes??
What is the genus and/or subgenus of plant proteins, and their corresponding working concentrations, that necessarily and predictably achieves the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, as opposed to the genus and/or subgenus of plant proteins, and their corresponding working concentrations, that do not necessarily and predictably achieve the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes??
What is the genus and/or subgenus of animal proteins, and their corresponding working concentrations, that necessarily and predictably achieves the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, as opposed to the genus and/or subgenus of animal proteins, and their corresponding working concentrations, that do not necessarily and predictably achieve the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes??
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves an enormously vast genus of structurally undisclosed proteins [structure 2] encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, each [structure 2] protein present in the product-by-process step(s) at an enormously vast range of structurally unrecited and undisclosed working concentrations, whereby the protein is present in a very low amount, essentially little to close-to-none, as there is no lower limit, or may be present in a very high amount, e.g. 10mM, 100mM, 1M, 5M, 10M, etc…, as there is no upper limit, respectively.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Essentially, Applicant is requiring the ordinary artisan to discover and invent for themselves that which Applicant simply does not possess, nor has disclosed.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
7. Claims 1 and 3-4 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 enablement requirement. The claim(s) contains subject matter which was not described in the specification in such a way as to enable one skilled in the art to which it pertains, or with which it is most nearly connected, to make and/or use the invention.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, written description rejections.
In Amgen, Inc., v. Sanofi (872 F.3d 1367 (2017)
At 1375, [T]he use of post-priority-date evidence to show that a patent does not disclose a representative number of species of a claimed genus is proper.
At 1377, [W]e questioned the propriety of the "newly characterized antigen" test and concluded that instead of "analogizing the antibody-antigen relationship to a `key in a lock,'" it was more apt to analogize it to a lock and "a ring with a million keys on it." Id. at 1352.
An adequate written description must contain enough information about the actual makeup of the claimed products — "a precise definition, such as by structure, formula, chemical name, physical properties, or other properties, of species falling within the genus sufficient to distinguish the genus from other materials," which may be present in "functional" terminology "when the art has established a correlation between structure and function." Ariad, 598 F.3d at 1350. But both in this case and in our previous cases, it has been, at the least, hotly disputed that knowledge of the chemical structure of an antigen gives the required kind of structure-identifying information about the corresponding antibodies. See, e.g., J.A. 1241 (549:5-
16) (Appellants' expert Dr. Eck testifying that knowing "that an antibody binds to a particular amino acid on PCSK9 ... does not tell you anything at all about the structure of the antibody"); J.A. 1314 (836:9-11) (Appellees' expert Dr. Petsko being informed of Dr. Eck's testimony and responding that "[m]y opinion is that [he's] right"); Centocor, 636 F.3d at 1352 (analogizing the antibody-antigen relationship as searching for a key "on a ring with a million keys on it") (internal citations and quotation marks omitted).
In the instant case, knowing that the initial protein [structure 2] is to confer the functional property [function 1] of a shelf-life of up to four years without refrigeration on the lyophilized exosomes, does not tell you anything at all about the structure (amino acid sequences) of the enormously vast genus of structurally undisclosed proteins [structure 2] encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, that will necessarily and predictably achieve the instantly recited functional property of the lyophilized exosome composition having a shelf life of up to four years without refrigeration [function 1], encompassed by the claims.
In Amgen, Inc., v. Sanofi (U.S. Supreme Court, No. 21-757 (2023))
“Amgen seeks to monopolize an entire class of things defined by their function”.
“The record reflects that this class of antibodies does not include just the 26 that Amgen has described by their amino acid sequence, but a “vast” number of additional antibodies that it has not.”
“It freely admits that it seeks to claim for itself an entire universe of antibodies.”
In the instant case, the record reflects that Applicant seeks to claim for themselves an enormously vast genus of structurally undisclosed proteins [structure 2] encoded by the about 20,000 to 25,000 different genes in the about 8.7x10^6 different species of eukaryotes, respectively, each [structure 2] protein present in the product-by-process step(s) at an enormously vast range of structurally unrecited and undisclosed working concentrations, whereby the protein is present in a very low amount, essentially little to close-to-none, as there is no lower limit, or may be present in a very high amount, e.g. 10mM, 100mM, 1M, 5M, 10M, etc…, as there is no upper limit, respectively.
“They leave a scientist forced to engage in painstaking experimentation to see what works. 159 U.S., at 475.
This is not enablement. More nearly, it is “a hunting license”. Brenner v. Manson, 383 U.S. 519, 536 (1966).
“Amgen has failed to enable all that it has claimed, even allowing for a reasonable degree of experimentation”.
While the “roadmap” would produce functional combinations, it would not enable others to make and use the functional combinations; it would instead leave them to “random trial-and-error discovery”.
“Amgen offers persons skilled in the art little more than advice to engage in “trial and error”.
“The more a party claims for itself the more it must enable.”
“Section 112 of the Patent Act reflects Congress’s judg-ment that if an inventor claims a lot, but enables only a lit-tle, the public does not receive its benefit of the bargain. For more than 150 years, this Court has enforced the stat-utory enablement requirement according to its terms. If the Court had not done so in Incandescent Lamp, it might have been writing decisions like Holland Furniture in the dark. Today’s case may involve a new technology, but the legal principle is the same.
Essentially, Applicant is requiring the ordinary artisan to discover and invent for themselves that which Applicant simply does not possess, nor has disclosed.
Thus, for the reasons outlined above, it is concluded that the claims do not meet the requirements for written description under 35 U.S.C. 112, first paragraph.
MPEP 2163 - 35 U.S.C. 112(a) and the first paragraph of pre-AIA 35 U.S.C. 112 require that the “specification shall contain a written description of the invention ....” This requirement is separate and distinct from the enablement requirement. Ariad Pharm., Inc. v. Eli Lilly & Co., 598 F.3d 1336, 1340, 94 USPQ2d 1161, 1167 (Fed. Cir. 2010) (en banc)
Dependent claims are included in the basis of the rejection because they do not correct the primary deficiencies of the independent claim(s).
Claim Rejections - 35 USC § 102
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 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.
8. Claims 1 and 3-4 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Seow et al (U.S. 2013/0053426; of record).
The recitation of a process limitation in Claim 1 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 1 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 1, Seow et al disclosed exosomes loaded with genetic material comprising nucleic acids for gene therapy and gene silencing (e.g. [0006]), wherein said exosomes are purified (e.g. [0092], “to purify the exosomes”; [0122], “then purified the exosomes”).
Seow et al successfully demonstrated the ability to introduce a heterologous therapeutic molecule into exosomes, e.g. transfecting the host cell with a nucleic acid expressing said therapeutic molecule, or electroporating said exosome (e.g. [0017-18, 90, 92]).
Seow et al disclosed wherein the exosomes have a diameter between 30nm and 100nm, or as large as 200nm (e.g. [0025]), with a size distribution peaking at 80nm (e.g. [0077]).
With respect to Claim 3, Seow et al disclosed examples of heterologous nucleic acids such as plasmid DNA and RNAi molecules (paragraphs [0033], [0037]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16). Seow et al disclosed, for example, a working example of transfecting or electroporating exosomes with a chemically unmodified plasmid [0112-113].
With respect to Claim 4, Seow et al disclosed the heterologous nucleic acids for gene therapy include treatment of hemophilia B, cystic fibrosis or spinal muscular atrophy [0035], and thus the ordinary artisan would have reasonably inferred the gene therapy nucleic acid to encode a therapeutic protein such as Factor IX, CFTR, or SMN-1.
Thus, Seow et al anticipate the claims.
9. Claims 1, 3-4, and 14-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Wood et al (U.S. 2014/0348904; of record).
The recitation of a process limitation in Claim 1 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 1 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 1, Wood disclosed cells for production of exosomes that are transfected with a polynucleotide construct encoding a fusion protein such that exosomes produced by the cells target the desired tissue/cell ([0075]), wherein said exosomes are purified (e.g. [0025], “exosome preparation that has already been isolated from cells”).
Wood et al successfully demonstrated the ability to introduce a heterologous therapeutic molecule into exosomes, e.g. transfecting the host cell with a nucleic acid expressing said therapeutic molecule (e.g. [0075]; Examples 1-2), or electroporating said exosome (e.g. [0040]; Example 2).
Wood et al disclosed wherein the exosomes have a diameter between 30nm and 100nm, or as large as 200nm (e.g. [0017]).
With respect to Claim 3, Wood et al disclosed examples of heterologous nucleic acids such as plasmid DNA and RNAi molecules ([0025]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16). Wood et al disclosed, for example, a working example of exosomes loaded with a chemically unmodified siRNA (Example 2, [0094-95]).
With respect to Claim 4, Wood et al disclosed the heterologous nucleic acids for gene therapy include treatment of hemophilia B, cystic fibrosis or spinal muscular atrophy [0030], and thus the ordinary artisan would have reasonably inferred the gene therapy nucleic acid to encode a therapeutic protein such as Factor IX, CFTR, or SMN-1.
Thus, Wood et al anticipate the claims.
10. Claims 1, 3-4, and 14-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Larocca et al., (U.S. Pub 2016/010368; of record).
The recitation of a process limitation in Claim 1 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 1 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 1, Larocca et al disclosed exosomes derived from progenitor cells (paragraph [0002]), comprising therapeutic molecules such as nucleic acids, proteins, peptides, small molecules such as drugs and the like ([0127]), wherein the exosomes are purified (e.g. [0244], “The purified exosomes”; [0249], “exosome particles in a purified preparation of exosomes”).
Larocca et al disclosed the ability to introduce a heterologous therapeutic molecule into exosomes, e.g. transfecting the host cell with a nucleic acid expressing said therapeutic molecule (e.g. [0050-52]).
Larocca et al disclosed wherein the exosomes have a diameter between 80nm and 110nm, with a predominant peak around 85-91nm (e.g. [0226]).
With respect to Claim 3, Larocca et al disclosed exosomes comprising therapeutic molecules such as small molecules, nucleic acids such as DNA, RNA, include mRNA and miRNA ([0127];[0128]; [0146]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16).
With respect to Claim 4, Larocca et al disclosed exosomes comprising therapeutic nucleic acid molecules such as mRNA, whereby those of ordinary skill in the art immediately recognize mRNA to encode peptides or proteins.
Thus, Larocca et al anticipate the claims.
11. Claims 1, 3, and 14-17 are rejected under 35 U.S.C. 102(a)(1) as being anticipated by Law et al (U.S. 2017/0252379; of record).
The recitation of a process limitation in Claim 1 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 1 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
With respect to Claim 1, Law et al disclosed compositions comprising placenta-derived adherent cell exosomes ([0003, 35]) comprising one or more nucleic acids comprising a small interfering RNA (siRNA) or an miRNA or one or more gene-modifying components, e.g. gRNA ([0031]-[0032]) loaded into said exosomes (e.g. [0247]), whereby said exosomes are purified (e.g. [0260], “The purified exosomes”; Example 3).
Law et al disclosed the ability to introduce a heterologous therapeutic molecule into exosomes e.g. by electroporation of the exosomes (e.g. [0029]).
Law et al disclosed wherein the exosomes have a diameter between 50nm and 200nm, with a predominant peak around 108-116nm (e.g. Figure 2B) or a diameter between 50-150nm or 70-150nm (e.g. [0182, 205]).
With respect to Claim 3, Law et al disclosed that “e.g., pharmaceutical agent, loaded into the placenta-derived adherent cell exosomes described herein comprises one or more nucleic acids. In specific embodiments, the one or more nucleic acids comprise a siRNA or a miRNA” ([0033]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16).
Thus, Law et al anticipate the claims.
Response to Arguments
Applicant argues that the none of Seow, Wood, Larocca, or Law teach/disclose the Product-by-Process steps.
Applicant’s argument(s) has been fully considered, but is not persuasive. The recitation of a process limitation in Claim 1 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claim 1 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
Applicant fails to provide objective evidence as to how the exosomes produced by the instantly recited process steps is/are materially, structurally, and/or functionally different from the prior art exosomes modified to comprise a heterologous therapeutic component.
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.
12. Claims 1 and 3-4 on the ground of nonstatutory double patenting as being unpatentable over claims 24-27 of U.S. Patent No. 10,596,123 in view of Seow et al (U.S. 2013/0053426; of record) and Law et al (U.S. 2017/0252379; of record).
‘123 claims a composition comprising microvesicles according to the method of claim 1, said composition further comprising a carrier. ‘123 claims wherein the microvesicles comprising platelet exosome material and an encapsulant.
‘123 does not claim wherein the exosomes are loaded with a heterologous therapeutic molecule.
However, prior to the effective filing date of the instantly claimed invention, Seow et al disclosed exosomes loaded with genetic material comprising nucleic acids for gene therapy and gene silencing (e.g. [0006]), wherein said exosomes are purified (e.g. [0092], “to purify the exosomes”; [0122], “then purified the exosomes”).
Seow et al successfully demonstrated the ability to introduce a heterologous therapeutic molecule into exosomes, e.g. transfecting the host cell with a nucleic acid expressing said therapeutic molecule, or electroporating said exosome (e.g. [0017-18, 90, 92]).
Similarly, Law et al disclosed compositions comprising placenta-derived adherent cell exosomes ([0003, 35]) comprising one or more nucleic acids comprising a small interfering RNA (siRNA) or an miRNA or one or more gene-modifying components, e.g. gRNA ([0031]-[0032]) loaded into said exosomes (e.g. [0247]), whereby said exosomes are purified (e.g. [0260], “The purified exosomes”; Example 3).
Law et al disclosed the ability to introduce a heterologous therapeutic molecule into exosomes e.g. by electroporation of the exosomes (e.g. [0029]).
‘123 does not recite the Product-by-Process steps of the instant claims.
However, the recitation of a process limitation in Claims 1 and 14-17 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claims 1 and 14-17 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instantly claimed Product-by-Process steps are recited at a high level of generality, and Applicant fails to provide objective evidence as to how the exosomes produced by the instantly recited process steps is/are materially, structurally, and/or functionally different from the prior art exosomes, including the ‘123 exosomes, modified to comprise a heterologous therapeutic component.
It would have been obvious to one of ordinary skill in the art to modify the exosomes of ‘123 to further comprise a heterologous therapeutic molecule with a reasonable expectation of success because those of ordinary skill in the art had long-recognized and successfully reduced to practice the ability to modify exosomes to comprise the artisan’s therapeutic molecule of interest.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 3, Seow et al disclosed examples of heterologous nucleic acids such as plasmid DNA and RNAi molecules (paragraphs [0033], [0037]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16). Seow et al disclosed, for example, a working example of transfecting or electroporating exosomes with a chemically unmodified plasmid [0112-113].
Law et al disclosed that “e.g., pharmaceutical agent, loaded into the placenta-derived adherent cell exosomes described herein comprises one or more nucleic acids. In specific embodiments, the one or more nucleic acids comprise a siRNA or a miRNA” ([0033]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16).
With respect to Claim 4, Seow et al disclosed the heterologous nucleic acids for gene therapy include treatment of hemophilia B, cystic fibrosis or spinal muscular atrophy [0035], and thus the ordinary artisan would have reasonably inferred the gene therapy nucleic acid to encode a therapeutic protein such as Factor IX, CFTR, or SMN-1.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
13. Claims 1 and 3-4 are rejected on the ground of nonstatutory double patenting as being unpatentable over claims 35-37 of U.S. Patent No. 12,036,325 in view of Seow et al (U.S. 2013/0053426; of record) and Law et al (U.S. 2017/0252379; of record).
‘325 claims a composition comprising a purified exosome product, wherein said exosomes are spherical or spheroidal.
‘325 does not claim wherein the exosomes are loaded with a heterologous therapeutic molecule.
However, prior to the effective filing date of the instantly claimed invention, Seow et al disclosed exosomes loaded with genetic material comprising nucleic acids for gene therapy and gene silencing (e.g. [0006]), wherein said exosomes are purified (e.g. [0092], “to purify the exosomes”; [0122], “then purified the exosomes”).
Seow et al successfully demonstrated the ability to introduce a heterologous therapeutic molecule into exosomes, e.g. transfecting the host cell with a nucleic acid expressing said therapeutic molecule, or electroporating said exosome (e.g. [0017-18, 90, 92]).
Similarly, Law et al disclosed compositions comprising placenta-derived adherent cell exosomes ([0003, 35]) comprising one or more nucleic acids comprising a small interfering RNA (siRNA) or an miRNA or one or more gene-modifying components, e.g. gRNA ([0031]-[0032]) loaded into said exosomes (e.g. [0247]), whereby said exosomes are purified (e.g. [0260], “The purified exosomes”; Example 3).
Law et al disclosed the ability to introduce a heterologous therapeutic molecule into exosomes e.g. by electroporation of the exosomes (e.g. [0029]).
‘325 does not recite the Product-by-Process steps of the instant claims.
However, the recitation of a process limitation in Claims 1 and 14-17 is/are not viewed as positively limiting the claimed product absent a showing that the process of making recited in Claims 1 and 14-17 imparts a novel or unexpected property to the claimed product of exosomes comprising a heterologous therapeutic component as it is assumed that equivalent products are obtainable by multiple routes. The burden is placed upon the applicants to establish a patentable distinction between the claimed and referenced products. The method in which the exosomes comprising a heterologous therapeutic component were produced is immaterial to their patentability.
"Even though product-by-process claims are limited by and defined by the process, determination of patentability is based on the product itself. The patentability of a product does not depend on its method of production. If the product in the product-by-process claim is the same or obvious from a product of the prior art, the claim is unpatentable even though the prior product was made by a different process." In re Thorpe, 227 USPQ 964, 966 (Fed. Cir. 1985). See also MPEP §2113.
See also discussions above per the 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The instantly claimed Product-by-Process steps are recited at a high level of generality, and Applicant fails to provide objective evidence as to how the exosomes produced by the instantly recited process steps is/are materially, structurally, and/or functionally different from the prior art exosomes, including the ‘325 exosomes, modified to comprise a heterologous therapeutic component.
It would have been obvious to one of ordinary skill in the art to modify the exosomes of ‘123 to further comprise a heterologous therapeutic molecule with a reasonable expectation of success because those of ordinary skill in the art had long-recognized and successfully reduced to practice the ability to modify exosomes to comprise the artisan’s therapeutic molecule of interest.
It is proper to "take account of the inferences and creative steps that a person of ordinary skill in the art would employ." KSR Int'l Co. v. Teleflex Inc., 127 S. Ct. 1727, 1741,82 USPQ2d 1385, 1396 (2007). See also Id. At 1742, 82 USPQ2d 1397 ("A person of ordinary skill is also a person of ordinary creativity, not an automaton.").
It should be noted that the KSR case forecloses the argument that a specific teaching, suggestion, or motivation is required to support a finding of obviousness. See the recent Board decision Ex parte Smith, —USPQ2d—, slip op. at 20, (Bd. Pat. App. & Interf. June 25, 2007) (citing KSR, 82 USPQ2d at 1396) (available at http: www. uspto.gov/web/offices/dcom/bpai/prec/fd071925 .pdf).
With respect to Claim 3, Seow et al disclosed examples of heterologous nucleic acids such as plasmid DNA and RNAi molecules (paragraphs [0033], [0037]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16). Seow et al disclosed, for example, a working example of transfecting or electroporating exosomes with a chemically unmodified plasmid [0112-113].
Law et al disclosed that “e.g., pharmaceutical agent, loaded into the placenta-derived adherent cell exosomes described herein comprises one or more nucleic acids. In specific embodiments, the one or more nucleic acids comprise a siRNA or a miRNA” ([0033]). The nucleic acids are considered to be “native”, in that they are not required to be chemically modified, as per instant specification (pg 4, lines 15-16).
With respect to Claim 4, Seow et al disclosed the heterologous nucleic acids for gene therapy include treatment of hemophilia B, cystic fibrosis or spinal muscular atrophy [0035], and thus the ordinary artisan would have reasonably inferred the gene therapy nucleic acid to encode a therapeutic protein such as Factor IX, CFTR, or SMN-1.
The cited prior art meets the criteria set forth in both Graham and KSR, and the teachings of the cited prior art provide the requisite teachings and motivations with a clear, reasonable expectation of success. Thus, the invention as a whole is prima facie obvious.
Conclusion
14. Claims 1 and 3-4 are rejected.
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KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638
Prosecution Insights