DETAILED ACTION
Applicants’ arguments, filed 25 February 2026, have been fully considered. Rejections and/or objections not reiterated from previous office actions are hereby withdrawn. The following rejections and/or objections are either reiterated or newly applied. They constitute the complete set presently being applied to the instant application.
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Claim Interpretation
Claim 23 recites the phrase “500 units.” As best understood by the examiner, this refers to 5000 individual molecules. This can also be written based upon conversion with Avogardo’s number as
500
m
o
l
e
c
u
l
e
s
1
×
1
m
o
l
6.02
×
10
23
m
o
l
e
c
u
l
e
s
=
8.3
×
10
-
22
m
o
l
This is the minimum amount of active that must be loaded into a single cell; the examiner notes that the units in the above calculations are moles, not moles per liter.
Claim 38 recites that the Kolmogorov length is about 35pm. The examiner notes that the term “pm” is a well-known abbreviation for picometers. A picometer is one one-thousandth of a nanometer and 1 one-millionth of a micron. As such, 35 pm is 0.035 nm or 0.000035 μm.
Claim Interpretation – Issues Related to 35 U.S.C. 112(f)
The following is a quotation of 35 U.S.C. 112(f):
(f) Element in Claim for a Combination. – An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The following is a quotation of pre-AIA 35 U.S.C. 112, sixth paragraph:
An element in a claim for a combination may be expressed as a means or step for performing a specified function without the recital of structure, material, or acts in support thereof, and such claim shall be construed to cover the corresponding structure, material, or acts described in the specification and equivalents thereof.
The claims in this application are given their broadest reasonable interpretation using the plain meaning of the claim language in light of the specification as it would be understood by one of ordinary skill in the art. The broadest reasonable interpretation of a claim element (also commonly referred to as a claim limitation) is limited by the description in the specification when 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is invoked.
As explained in MPEP § 2181, subsection I, claim limitations that meet the following three-prong test will be interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph:
(A) the claim limitation uses the term “means” or “step” or a term used as a substitute for “means” that is a generic placeholder (also called a nonce term or a non-structural term having no specific structural meaning) for performing the claimed function;
(B) the term “means” or “step” or the generic placeholder is modified by functional language, typically, but not always linked by the transition word “for” (e.g., “means for”) or another linking word or phrase, such as “configured to” or “so that”; and
(C) the term “means” or “step” or the generic placeholder is not modified by sufficient structure, material, or acts for performing the claimed function.
Use of the word “means” (or “step”) in a claim with functional language creates a rebuttable presumption that the claim limitation is to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites sufficient structure, material, or acts to entirely perform the recited function.
Absence of the word “means” (or “step”) in a claim creates a rebuttable presumption that the claim limitation is not to be treated in accordance with 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. The presumption that the claim limitation is not interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, is rebutted when the claim limitation recites function without reciting sufficient structure, material or acts to entirely perform the recited function.
Claim limitations in this application that use the word “means” (or “step”) are being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action. Conversely, claim limitations in this application that do not use the word “means” (or “step”) are not being interpreted under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph, except as otherwise indicated in an Office action.
In this case, claim interpretation under 35 U.S.C. 112(f) has been invoked, and the phrase of the steps of “vesiculation” and “isolating” in claim 23 will be interpreted in view of 35 U.S.C. 112(f) because the claim does not recite sufficient structure, material, or acts for performing the claimed function. As such, the phrase “vesiculation” is understood to be limited to the types of vesiculation techniques described in the instant specification on page 56, lines 13-24 and in the examples.
This new claim interpretation issue has been necessitated by the claim amendments.
Claim Rejections - 35 USC § 112(b) – Indefiniteness
The following is a quotation of 35 U.S.C. 112(b):
(b) CONCLUSION.—The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the inventor or a joint inventor regards as the invention.
The following is a quotation of 35 U.S.C. 112 (pre-AIA ), second paragraph:
The specification shall conclude with one or more claims particularly pointing out and distinctly claiming the subject matter which the applicant regards as his invention.
Claims 23-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim limitation “isolating the CLRCEVs [i.e. cargo-loaded red cell extracellular vesicles]” invokes 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph. However, the written description fails to disclose the corresponding structure, material, or acts for performing the entire claimed function and to clearly link the structure, material, or acts to the function. The term “isolating” is interpreted under 35 U.S.C. 112(f) in view of the claim language “comprising the steps of” in claim 23”; however, the instant specification does not appear to provide a disclosure of how this step occurs. Therefore, the claim is indefinite and is rejected under 35 U.S.C. 112(b) or pre-AIA 35 U.S.C. 112, second paragraph.
Applicant may:
(a) Amend the claim so that the claim limitation will no longer be interpreted as a limitation under 35 U.S.C. 112(f) or pre-AIA 35 U.S.C. 112, sixth paragraph;
(b) Amend the written description of the specification such that it expressly recites what structure, material, or acts perform the entire claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(c) Amend the written description of the specification such that it clearly links the structure, material, or acts disclosed therein to the function recited in the claim, without introducing any new matter (35 U.S.C. 132(a)).
If applicant is of the opinion that the written description of the specification already implicitly or inherently discloses the corresponding structure, material, or acts and clearly links them to the function so that one of ordinary skill in the art would recognize what structure, material, or acts perform the claimed function, applicant should clarify the record by either:
(a) Amending the written description of the specification such that it expressly recites the corresponding structure, material, or acts for performing the claimed function and clearly links or associates the structure, material, or acts to the claimed function, without introducing any new matter (35 U.S.C. 132(a)); or
(b) Stating on the record what the corresponding structure, material, or acts, which are implicitly or inherently set forth in the written description of the specification, perform the claimed function. For more information, see 37 CFR 1.75(d) and MPEP §§ 608.01(o) and 2181.
Claim 34 is rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claim 34 recites that the hypertonic solution is an isotonic solution. This is unclear because the skilled artisan would have understood the phrase “hypertonic” to refer to a salt concentration exceeding that of blood plasma, whereas isotonic refers to a salt concentration equal to that of blood plasma. As such, the skilled artisan would have understood hypertonic and isotonic solutions to have been mutually exclusive categories. As such, it is unclear how a hypertonic solution could have also been isotonic.
For the purposes of examination under prior art, the examiner will proceed with the understanding that claim 34 has the same scope as claim 26 upon which it depends.
Claims 36-39 are rejected under 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, as being indefinite for failing to particularly point out and distinctly claim the subject matter which the inventor or a joint inventor (or for applications subject to pre-AIA 35 U.S.C. 112, the applicant), regards as the invention.
Claims 36 and 38 recite “A method of producing the plurality of cargo loaded red cell extracellular vesicles…” That the claim recites the term “the” would appear to indicate that the claim is reciting cargo loaded red blood cell extracellular vesicles from a dependent claim. However, claims 36 and 38 are independent claims which do not depend from a parent claim. As such, it appears that there is no antecedent basis for the claimed requirement reciting “the plurality of cargo loaded red cell extracellular vesicles.”
For the purposes of examination under prior art, the examiner will examine claims 36 and 38 as if the claims recite “A method for producing a plurality of cargo loaded red cell extracellular vesicles…” The examiner recommends that both claims 36 and 38 be amended to remove the word “the” and to replace with the word “a” in order to overcome this rejection.
Claim Rejections - 35 USC § 103 – Obviousness
The following is a quotation of 35 U.S.C. 103 which forms the basis for all obviousness rejections set forth in this Office action:
A patent for a claimed invention may not be obtained, notwithstanding that the claimed invention is not identically disclosed as set forth in section 102, if the differences between the claimed invention and the prior art are such that the claimed invention as a whole would have been obvious before the effective filing date of the claimed invention to a person having ordinary skill in the art to which the claimed invention pertains. Patentability shall not be negated by the manner in which the invention was made.
The factual inquiries for establishing a background for determining obviousness under 35 U.S.C. 103 are summarized as follows:
1. Determining the scope and contents of the prior art.
2. Ascertaining the differences between the prior art and the claims at issue.
3. Resolving the level of ordinary skill in the pertinent art.
4. Considering objective evidence present in the application indicating obviousness or nonobviousness.
This application currently names joint inventors. In considering patentability of the claims the examiner presumes that the subject matter of the various claims was commonly owned as of the effective filing date of the claimed invention(s) absent any evidence to the contrary. Applicant is advised of the obligation under 37 CFR 1.56 to point out the inventor and effective filing dates of each claim that was not commonly owned as of the effective filing date of the later invention in order for the examiner to consider the applicability of 35 U.S.C. 102(b)(2)(C) for any potential 35 U.S.C. 102(a)(2) prior art against the later invention.
Claim(s) 23-28 and 30-37 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (WO 2020/060496 A1) in view of Magnani (“Erythrocyte Engineering for Drug Delivery and Targeting” Landes Bioscience, 2002, pages 1-141 and 10 additional pages).
Shi et al. (hereafter referred to as Shi) is drawn to extracellular vesicles loaded with drugs, as of Shi, title, abstract, and figure in abstract.
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Shi is drawn to red blood cell extracellular vesicles, as of Shi, page 10, starting at about lines 8-9. Regarding loading the drugs or other cargo, Shi teaches the following as of pages 23-24, relevant text reproduced below.
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As such, the skilled artisan would have been motivated to have conducted a method in which the cargo was loaded into the red blood cell before formation, followed by production of the loaded red blood cell extracellular vesicle, as of the Shi on page 24 top paragraph. Shi also teaches vesiculation to form extracellular vesicles as of at least page 11 of Shi.
Shi is not anticipatory because Shi does not exemplify a method of loading the red blood cells with cargo prior to formation of red blood cell extracellular vesicles.
Magnani teaches methods of loading drugs into erythrocytes, including the following, as of Magnani, page 2, relevant text reproduced below.
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Magnani also teaches vesiculation at least as of page 79.
As such, Magnani teaches loading of an erythrocyte with active agents.
As best understood by the examiner, Magnani differs from the claimed invention because, while Magnani teaches vesiculation of red blood cells on page 79, Magnani does not teach vesiculation of red blood cells with an external agent loaded therein.
It would have been prima facie obvious for one of ordinary skill in the art to have formed extracellular vesicles, as of Shi, from a red blood cell with an active agent loaded in the manner taught by Magnani. Shi is drawn to the formation of red blood cell extracellular vesicles loaded with active agent, and teaches that these can be made by forming extracellular vesicles from red blood cells already loaded with active agent (though this is a non-preferred method). Magnani teaches formation of red blood cells loaded with active agent. As such, the skilled artisan would have been motivated to have loaded a red blood cell with an active agent then produced extracellular vesicles therefrom in order to have predictably obtained red blood cell extracellular vesicles comprising an active agent, which is the desired product of Shi, with a reasonable expectation of success.
As to claim 23, part (a), Magnani teaches providing cargo-loaded red blood cells, as of at least page 2 of Magnani as well as elsewhere in the reference.
As to claim 23 part (b), Shi teaches production of extracellular vesicles loaded with cargo as of pages 23-24, text reproduced above.
As to claim 23 part (c), Shi teaches isolating extracellular vesicles, as of at least the bottom paragraph of page 11 of Shi, wherein Shi teaches centrifugation for use in such an isolation process.
As to claim 23, the claim requires that the red blood cells are loaded with cargo prior to vesiculation. Shi appears to teach that in the preferable method, vesiculation (i.e. formation of extracellular vesicles) occurs prior to loading of the cargo, as of Shi, paragraph bridging pages 23-24, relevant text reproduced above. Nevertheless, it is the examiner’s understanding from this that loading the cargo prior to formation of extracellular vesicles is a non-preferred method of Shi. A known or obvious composition (or in this case method) does not become patentable simply because it has been described as somewhat inferior to some other product for the same use; see MPEP 2123(II). Additionally, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results; see MPEP 2144.04(IV)(C).
As to claim 23, the claim requires a particular particle size range. Shi teaches the following as of figure 1d, reproduced below.
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This particle size range appear to be within the size required by claim 23.
As to claim 23, the claim requires at least about 500 units of cargo per red blood cell prior to vesiculation. As best understood, the phrase “500 units” refers to 500 individual molecules, or 8.3 X 10-22 moles; see the “Claim Interpretation” section above. As best understood by the examiner, the amount loaded would have varied with the type of active agents, with a red blood cell being able to load more molecules of cargo if the cargo is a small molecule and fewer molecules if the cargo is a large molecule. While Shi is primarily drawn to loading larger nucleic acids, Shi also teaches loading small molecules as of page 6 lines 19-23. Magnani also teaches loading small molecules such as methotrexate, as of Magnani, page 21, bottom of page. As such, the skilled artisan would have been motivated to have loaded at least 500 molecules per cargo, especially when small molecules are used as the cargo, which is taught by both Shi and Magnani. As such, the amount of cargo loaded appears to be a function of optimization of the active agent loaded. Where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of loading a red blood cell with drug are taught by Magnani. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the amount of drug that could be loaded via routine experimentation. This is especially the case since the amount of drug that can be loaded would be heavily dependent upon the size of the drug, and both Shi and Magnani teach loading a wide variety of drugs.
As to claim 24, Magnani teaches electroporation, hypotonic hemolysis, and the osmotic pulse method as of page 2, relevant text reproduced above.
As to claim 25, Magnani teaches isotonic resealing as of page 90, as well as elsewhere in Chapter 7 of Magnani. The examiner understands the phrase “isotonic resealing” to read on the additional limitations of claim 25.
As to claim 26, Magnani teaches the following process on page 6:
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Magnani teaches the dialysis process on page 7, which is reproduced below.
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As to claim 26, step (a), Magnani teaches an isotonic solution with a hematocrit that overlaps with the claimed hematocrit, as of the above-reproduced text. Magnani teaches the required low temperature of 4°C for lysis as of Magnani, page 8, 7th to last line. While the prior art does not disclose the exact claimed values, but does overlap: in such instances even a slight overlap in range establishes a prima facie case of obviousness. See MPEP 2144.05(I).
As to claim 26, part (b), Magnani teaches combining red cells with the substance to be loaded and the cargo, as of the above-reproduced text.
As to claim 26, part (c), Magnani teaches a hypotonic solution (50x erythrocyte volume), as of the above-reproduced paragraph on the 5th and 6th lines. While Magnani appears to be silent as to the osmolarity of this in terms of mOsm/L; nevertheless, that this solution is hypotonic is taught by Magnani. Where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of a hypotonic solution are taught by Magnani; as such, it would not have been inventive for the skilled artisan to have determined the exact osmolarity via routine experimentation.
As to claim 26, part (d), the result of this method would have allowed the substance to be encapsulated to enter red blood cells, as of Magnani, page 7, figure 4, reproduced below.
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As to claim 26, part (e), the dialysis bag of Magnani is understood to read on the required dialysis membrane. Additionally, Magnani teaches the following setup, as of Magnani, page 9, figure 6, relevant figure reproduced below.
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As best understood by the examiner, each turn of the rotator would appear to be a repetition of steps (b)-(d).
As to claim 26, part (f), Magnani teaches the following resealing method, as of page 7, bottom paragraph, reproduced below.
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This method entails isotonicity as well as heating to 37°C, which is within the required temperature range.
As to claim 27, Magnani appears to teach maintaining the temperature at 4°C for the lysis step, as of Magnani, page 7, 7th line from bottom.
As to claim 28, the hypotonic loading process of Magnani is understood to read on the requirement of this claim.
As to claims 30-31, Magnani teaches the following method on page 78, relevant text reproduced below with highlighting by the examiner.
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The above-reproduced method is for the production of nanoerythrocytes, which are abbreviated as “nEs” on the second line of the above-reproduced paragraph. The examiner understands the nanoerythrocytes of Magnani to read on the required RCEVs (Red cell extracellular vesicles) because nanoerythrocytes are nanosized particles made from a red blood cell membrane, which is the same thing as red cell extracellular vesicles. Magnani also teaches a 5 minute sonication time, as of the above-reproduced text.
As to claim 32, Shi teaches double stranded RNA as of page 25, line 3.
As to claim 33, Magnani teaches hypotonic hemolysis as of Magnani, page 5, last three lines and the entirety of page 6, wherein this process appears to be useful for loading a cargo to be encapsulated. Magnani also teaches first modifying erythrocytes to be under hypotonic conditions then restoring them to isotonic conditions via 0.9% saline before extrusion, as of Magnani, page 77.
As to claim 34, this claim is rejected for essentially the same reason that claim 26 is rejected. See the above rejection under 35 U.S.C. 112(b).
As to claim 35, Shi teaches the following on page 29.
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As such, Shi is understood to teach the required particle concentration.
As to claim 36(a), Shi teaches hypotonic hemolysis and loading as of the last few lines of page 5 as well as page 6. Shi teaches the following on page 6, with highlighting by the examiner.
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As such, Shi appears to teach hypotonic loading with isotonic resealing rather than hypertonic resealing.
As to claim 36(b), Shi appears to teach that in the preferable method, vesiculation (i.e. formation of extracellular vesicles) occurs prior to loading of the cargo, as of Shi, paragraph bridging pages 23-24, relevant text reproduced above. Nevertheless, it is the examiner’s understanding from this that loading the cargo prior to formation of extracellular vesicles is a non-preferred method of Shi. A known or obvious composition (or in this case method) does not become patentable simply because it has been described as somewhat inferior to some other product for the same use; see MPEP 2123(II). Additionally, the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results; see MPEP 2144.04(IV)(C).
As to claim 36(c), Shi teaches isolating extracellular vesicles, as of at least the bottom paragraph of page 11 of Shi, wherein Shi teaches centrifugation for use in such an isolation process.
As to the last three lines of claim 36, Shi teaches particles with the required size as of figure 1d of Shi, which is reproduced below. Regarding the number of units of cargo, the rationale applied to the rejection of claim 23 also applies to claim 36.
As to claim 37(b1), the rationale provided by the examiner regarding claim 35 also applies to part (b1) of claim 37.
As to claim 37(b2), the examiner understands the step of extrusion, e.g. as of at least page 79 of Maganani, to be drawn to agitating the liquid medium comprising the erythrocytes to achieve vesiculation because the shear force caused by the erythrocyte contacting a membrane used in the extrusion step would have caused agitation.
Claim(s) 29 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (WO 2020/060496 A1) in view of Magnani (“Erythrocyte Engineering for Drug Delivery and Targeting” Landes Bioscience, 2002, pages 1-141 and 10 additional pages), the combination further in view of Lodish et al. (WO 2014/183071 A2).
Shi is drawn to a method for preparing red blood cell extracellular vesicles comprising active agent loaded therein. Magnani is drawn to a method of preparing red blood cells with active agents loaded therein. See the above rejection over Shi in view of Magnani by themselves. Shi teaches the following, as of page 2, relevant text reproduced below.
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As best understood by the examiner, neither Shi nor Magnani teach engineered reticulocytes.
Lodish et al. (hereafter referred to as Lodish) is drawn to production of red blood cells in vitro engineered to comprise particular proteins, as of Lodish, title and abstract. The production of red blood cells of Lodish entails formation of reticulocytes, which are an intermediate in the formation of mature red blood cells, as of Lodish, page 9 line 29 through page 10, line 16. These reticulocytes appear to be engineered because they contain proteins not found in natural reticulocytes.
Lodish does not appear to teach the preparation of extracellular vesicles.
It would have been prima facie obvious for one of ordinary skill in the art to have provided the red blood cells used in the method of Shi in view of Magnani from the red blood cell precursors of Lodish. Shi in view of Magnani teach the formation of loaded red blood cells and/or vesicles produced therefrom, and Shi specifically cites WO 2014/183071 A2 as a source of red blood cells. As Lodish is WO 2014/183071 A2, the skilled artisan would have been motivated to have used red blood cells produced from the engineered red blood cell precursors of Lodish (including engineered reticulocytes) for predictable formation of the red blood cell extracellular vesicles of Shi and Magnani with a reasonable expectation of success.
Claim(s) 38-39 is/are rejected under 35 U.S.C. 103 as being unpatentable over Shi et al. (WO 2020/060496 A1) in view of Magnani (“Erythrocyte Engineering for Drug Delivery and Targeting” Landes Bioscience, 2002, pages 1-141 and 10 additional pages), the combination further in view of Gazeau et al. (WO 2019/002608 A1).
As an initial matter, Gazeau et al. (WO 2019/002608 A1) was written in French. However, Gazeau et al. (US 2020/0385665 A1) appears to be an English translation of Gazeau et al. (WO 2019/002608 A1). As such, all page and paragraph citations will be to Gazeau et al. (US 2020/0385665 A1); however, the material cited therein is understood by the examiner to have been present in Gazeau et al. (WO 2019/002608 A1).
Shi is drawn to a method for preparing red blood cell extracellular vesicles comprising active agent loaded therein. Magnani is drawn to a method of preparing red blood cells with active agents loaded therein. See the above rejection over Shi in view of Magnani by themselves. In both methods, Shi and Magnani produce extracellular vesicles from cells (i.e. vesiculating).
Neither Shi nor Magnani teach agitating for about 6 hours at a speed that causes a flow having a Kolmogorov length of about 35 pm.
Gazeau et al. (hereafter referred to as Gazeau) is drawn to a system and method for producing extracellular vesicles from producer cells via agitation. Gazeau teaches the following, as of paragraphs 0012-0013, relevant text reproduced below.
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Also see Gazeau, paragraphs 0057, 0066-0067, 0070, and 0079 regarding the Kolmogorov length. Gazeau teaches agitating for preferably more than 2 hours, as of Gazeau, paragraph 0070.
It would have been prima facie obvious for one of ordinary skill in the art to have formed extracellular vesicles from cells, as taught by Shi and Magnani, using the method of Gazeau. Shi and Magnani are drawn to methods of producing loaded red blood cell derived extracellular vesicles from red blood cells. While Shi and Magnani teach various methods that cells are treated to form extracellular vesicles, Shi and Magnani appear to be silent regarding the Kolmogorov length associated with these methods. However, Gazeau is also drawn to formation of extracellular vesicles from cells, and Gazeau teaches the Kolmogorov length associated with treatment of said cells to form extracellular vesicles. As such, the skilled artisan would have been motivated to have treated the red blood cells of Shi and Magnani via a method having the Kolmogorov length and treatment time taught by Gazeau for predictable formation of extracellular vesicles with a reasonable expectation of success.
As to claim 38, part (a), Magnani teaches providing cargo-loaded red blood cells, as of at least page 2 of Magnani as well as elsewhere in the reference.
As to claim 38 part (b), Shi teaches production of extracellular vesicles loaded with cargo as of pages 23-24, text reproduced above. Upon the modifications of Gazeau, the resultant method would have used a method of agitation comprising a Kolmogorov length and a time period.
As to claim 38 part (c), Shi teaches isolating extracellular vesicles, as of at least the bottom paragraph of page 11 of Shi, wherein Shi teaches centrifugation for use in such an isolation process.
As to claim 38, the claim requires at least 5000 units of cargo per cargo loaded red cell. As best understood by the examiner, the amount loaded would have varied with the type of active agents, with a red blood cell being able to load more molecules of cargo if the cargo is a small molecule and fewer molecules if the cargo is a large molecule. While Shi is primarily drawn to loading larger nucleic acids, Shi also teaches loading small molecules as of page 6 lines 19-23. Magnani also teaches loading small molecules such as methotrexate, as of Magnani, page 21, bottom of page. As such, the skilled artisan would have been motivated to have loaded at least 500 molecules per cargo, especially when small molecules are used as the cargo, which is taught by both Shi and Magnani. As such, the amount of cargo loaded appears to be a function of optimization of the active agent loaded. Where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of loading a red blood cell with drug are taught by Magnani. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the amount of drug that could be loaded via routine experimentation. This is especially the case since the amount of drug that can be loaded would be heavily dependent upon the size of the drug, and both Shi and Magnani teach loading a wide variety of drugs.
As to claim 38 parts (b1) and (b2), Gazeau teaches providing cells in a liquid medium and treating for multiple hours with a Kolmogorov length less than about 75-50 μm.
As to claim 38 part (c), the claim requires isolation of cargo loaded red cell extracellular vesicles. This is taught by Shi and Magnani; see the rejection above.
As to claim 38, the claim requires a diameter from about 100 nm to about 300 nm. This is taught by Shi, figure 1d, explained in greater detail above.
As to claim 38, the claim requires at least 500 units of cargo per cargo loaded red cell extracellular vesicle. As best understood, the phrase “500 units” refers to 500 individual molecules, or 8.3 X 10-22 moles; see the “Claim Interpretation” section above. As best understood by the examiner, the amount loaded would have varied with the type of active agents, with a red blood cell being able to load more molecules of cargo if the cargo is a small molecule and fewer molecules if the cargo is a large molecule. While Shi is primarily drawn to loading larger nucleic acids, Shi also teaches loading small molecules as of page 6 lines 19-23. Magnani also teaches loading small molecules such as methotrexate, as of Magnani, page 21, bottom of page. As such, the skilled artisan would have been motivated to have loaded at least 500 molecules per cargo, especially when small molecules are used as the cargo, which is taught by both Shi and Magnani. As such, the amount of cargo loaded appears to be a function of optimization of the active agent loaded. Where 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. See MPEP 2144.05(II)(A). In this case, the general conditions of loading a red blood cell with drug are taught by Magnani. As such, it would not have been inventive for the skilled artisan to have discovered the optimum or workable ranges of the amount of drug that could be loaded via routine experimentation. This is especially the case since the amount of drug that can be loaded would be heavily dependent upon the size of the drug, and both Shi and Magnani teach loading a wide variety of drugs.
As to claim 39, the claim requires at least 0.5 million cargo loaded red cells per mL. This claim is rejected for essentially the same reason that claim 35 is rejected.
Response to Arguments (Both Written and Verbal)
In applicant’s response on 25 February 2026 (hereafter referred to as applicant’s response), applicant makes arguments regarding the previously presented obviousness rejection. These arguments are addressed below. Additionally, an examiner-initiated interview was conducted; see the PTO-413 added to the file record on 28 April 2026. Various arguments made verbally by representative of applicant are also addressed here.
In applicant’s written response, page 8, applicant makes the following argument on the second to last paragraph, which is reproduced below; similar arguments are made as of the paragraph bridging pages 8-9.
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The examiner disagrees. Shi’s teaching that the cargo is preferably loaded after the vesicles have formed would appear to indicate that cargo can be loaded prior to the formation of the vesicle, even if this is not preferred. A known or obvious composition (or on this case, method) does not become patentable simply because it has been described as somewhat inferior to some other product (or in this case, method) for the same use. See MPEP 2145(X)(D)(1) and 2123(II).
Regarding the allegations of the art failing to enable a method in which the order is such that the cargo is loaded into the cell rather than into the extracellular vesicles after they have formed, this is not persuasive. When the reference relied on expressly anticipates or makes obvious all of the elements of the claimed invention, the reference is presumed to be operable. Once such a reference is found, the burden is on applicant to rebut the presumption of operability. See MPEP 2121(I). In this case, applicant’s arguments appear to assert that the prior art is inoperable, and are insufficient to meet applicant’s burden as per MPEP 2121(I).
Applicant then makes the following arguments on page 9, first full paragraph, relevant text reproduced below.
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In the first sentence of this paragraph, applicant argues that hypertonic resealing conditions after hypotonic loading is excluded by the claim. However, in the second paragraph in the above-reproduced text, applicant appears to take the position that any resealing conditions following hypotonic loading are excluded by the claim. Looking to claim 25, it appears that the claim only excludes hypertonic resealing, but does not exclude isotonic resealing. The prior art appears to teach isotonic resealing, which would not appear to be excluded by the claims.
Regarding claim 29, applicant argues that this claim is patentable for the same reason that claim 28 is allegedly patentable, and no additional arguments have been written regarding the Lodish secondary reference, as of applicant’s response, page 9. This is not persuasive. Claim 28 has been properly rejected for the reasons set forth above. As not additional arguments have been presented regarding the secondary references or dependent claims, the rejection of claim 29 has been maintained.
Applicant also presented arguments regarding alleged unexpected results; these were discussed briefly as of applicant’s response, page 9, second full paragraph, and were discussed to a greater extent in an examiner-initiated interview for which an interview summary has been added to the record on 28 April 2026. Issues related to alleged unexpected results have been discussed below.
In support of the position of alleged unexpected results, Tables 3 and 4 on pages 47-48 of the specification were discussed in the interview summarized as per the interview summary added to the record on 28 April 2026. These tables are reproduced below.
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During the interview, as best understood by the examiner, representative of applicant appeared to take the position that Table 3 is the inventive example, and Table 4, which is “mock” loaded, is the comparative example. As best understood by the examiner, during the course of the interview, representative of applicant appeared to take the position that Table 3 shows superior results as compared with Table 4.
The examiner takes the position that this comparative testing is not probative of non-obviousness. The examiner presents the following rationale in support of this position.
In order to overcome a prior art rejection based upon unexpected results, the claimed invention must be compared with the closest subject matter that actually exists in the prior art. See MPEP 716.02(e). In this case, the closest subject matter that actually exists in the prior art would appear to be a method of preparing cargo-loaded red cell extracellular vesicles wherein the vesicles are first produced from unloaded red blood cells (i.e. vesiculation) followed by loading of the cargo to the red blood cell extracellular vesicles. As such, the resultant product of the closest subject matter to exist in the prior art would appear to be cargo-loaded extracellular vesicles that have been loaded at a different stage in their preparation as compared with the claimed method. In contrast, the comparative example in the above-reproduced table appears to be mock-loaded extracellular vesicles, which are not loaded at all. As such, the comparative example appears to be further away from the instantly claimed method than are the methods of the cited prior art.
Additionally, it is unclear if the data show improved results. In support of this position, the examiner looks to Table 4, which is a comparative example, which shows yields in the range of about 33-48% and mean purified extracellular vesicles per mL in the range of 1 X 1011 to slightly higher than 1 X 1012. Looking to the inventive examples in Table 3, the examiner notes that Batch 1 shows yield values in the range of 27-44% and a maximum mean purified extracellular vesicles per mL of 1.05 X 1011. These results do not appear to be superior to those of comparative Table 4. With that being said, the examiner admits that Batch 2 of Table 3 shows results that exceed that of Table 4 both regarding yield as well as mean purified extracellular vesicles per mL. Batch 3 of Table 3 shows mean purified extracellular vesicles per mL exceeding that of comparative Table 4.
The burden is on applicant to establish that results are unexpected and of both statistical and practical significance. See MPEP 716.02(b)(I). The apparently poor results of Batch 1 of Table 3 appear to show that any improvements achieved by applicant do not appear to be of statistical significance.
According to MPEP 2144.04(IV)(C), the selection of any order of performing process steps is prima facie obvious in the absence of new or unexpected results. In this case, there do not appear to be unexpected results sufficient to show that the claimed order of performing process steps is unexpectedly superior to that of the prior art. As such, the previously applied rejection has not been withdrawn in view of unexpected results.
Conclusion
No claim is allowed.
Applicant's amendment necessitated the new ground(s) of rejection presented in this Office action. Accordingly, THIS ACTION IS MADE FINAL. See MPEP § 706.07(a). Applicant is reminded of the extension of time policy as set forth in 37 CFR 1.136(a).
A shortened statutory period for reply to this final action is set to expire THREE MONTHS from the mailing date of this action. In the event a first reply is filed within TWO MONTHS of the mailing date of this final action and the advisory action is not mailed until after the end of the THREE-MONTH shortened statutory period, then the shortened statutory period will expire on the date the advisory action is mailed, and any nonprovisional extension fee (37 CFR 1.17(a)) pursuant to 37 CFR 1.136(a) will be calculated from the mailing date of the advisory action. In no event, however, will the statutory period for reply expire later than SIX MONTHS from the mailing date of this final action.
Any inquiry concerning this communication or earlier communications from the examiner should be directed to ISAAC SHOMER whose telephone number is (571)270-7671. The examiner can normally be reached 7:30 AM to 5:00 PM Monday Through Friday.
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ISAAC . SHOMER
Primary Examiner
Art Unit 1612
/ISAAC SHOMER/ Primary Examiner, Art Unit 1612
Prosecution Insights