DETAILED ACTION
Notice of Pre-AIA or AIA Status
The present application, filed on or after March 16, 2013, is being examined under the first inventor to file provisions of the AIA .
Detailed Action
This action is in response to the papers filed November 10, 2025.
Amendments
Applicant's amendments, filed November 10, 2025, is acknowledged. Applicant has cancelled Claims 2-10, 12-32, 34-35, 38-39, 42-46, 48, 50-64, 66, and 68-73, amended Claims 1, 36, 65, 65, and 67, and withdrawn Claims 11, 40, 47, 67, and 74.
The amendment to the claims filed on November 10, 2025 does not comply with the requirements of 37 CFR 1.121(c) and 37 CFR 1.126.
Amendments to the claims filed on or after July 30, 2003 must comply with 37 CFR 1.121(c) which states:
(c) Claims. Amendments to a claim must be made by rewriting the entire claim with all changes (e.g., additions and deletions) as indicated in this subsection, except when the claim is being canceled. Each amendment document that includes a change to an existing claim, cancellation of an existing claim or addition of a new claim, must include a complete listing of all claims ever presented, including the text of all pending and withdrawn claims, in the application. The claim listing, including the text of the claims, in the amendment document will serve to replace all prior versions of the claims, in the application. In the claim listing, the status of every claim must be indicated after its claim number by using one of the following identifiers in a parenthetical expression: (Original), (Currently amended), (Canceled), (Withdrawn), (Previously presented), (New), and (Not entered).
(2) When claim text with markings is required. All claims being currently amended in an amendment paper shall be presented in the claim listing, indicate a status of "currently amended," and be submitted with markings to indicate the changes that have been made relative to the immediate prior version of the claims. The text of any added subject matter must be shown by underlining the added text. The text of any deleted matter must be shown by strike-through except that double brackets placed before and after the deleted characters may be used to show deletion of five or fewer consecutive characters. The text of any deleted subject matter must be shown by being placed within double brackets if strike-through cannot be easily perceived. Only claims having the status of "currently amended," or "withdrawn" if also being amended, shall include markings.
Claim 36 fails to provide the required markings of the amendment(s).
Claims 1, 11, 33, 36-37, 40-41, 47, 49, 65, 67, and 74-76 are pending.
Election/Restrictions
Applicant has elected without traverse the invention of Group I, Claims 1-2, 6, 11, 33, 36-37, 40-41, 44, 47, 49, 56, 61, 63-65, 67, and 74-75, drawn to a method for delivering a complex of two or more molecules into an immune cell, the method comprising the step(s) of:
i) passing a cell suspension comprising immune cells through a constriction, classified in CPC C12N 15/87.
Within Group I, Applicant has elected without traverse the following species, wherein:
i) the alternative molecule present in the complex is “one or more polypeptides”, as recited in Claims 36(a);
ii) the alternative complex formation context is “the complex is formed prior to the contacting”, as recited in Claim 44;
iii) the alternative immune cell is a “T cell”, as recited in Claim 75;
iv) the alternative contacting is “before the cell suspension passes through the constriction”, as recited in Claim 41;
v) the alternative contacting condition is “at a temperature ranging from about 0C to about 40C”, as recited in Claim 11; and
vi) the alternative complex functional property is “has a half-life in the cell suspension of about 1 minute to about 48 hours”, as recited in Claim 6.
Claims 1, 11, 33, 36-37, 40-41, 47, 49, 65, 67, and 74-76 are pending.
Claims 11, 40-41, 47, 67, and 74 are pending but withdrawn from further consideration pursuant to 37 CFR 1.142(b) as being drawn to a non-elected invention, there being no allowable generic or linking claim.
Claims 1, 33, 36-37, 49, 61, 65, and 75-76 are under consideration.
Priority
This application is a continuation of application 16/068,631 filed on July 6, 2018, now abandoned, which is a 371 of PCT/US2017/013055 filed on January 11, 2017. Applicant’s claim for the benefit of a prior-filed application provisional application 62/277,858 filed on January 12, 2016 under 35 U.S.C. 119(e) or under 35 U.S.C. 120, 121, or 365(c) 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 application, Application No. 62/277,858 filed on January 12, 2016 fails 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.
Claim 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium at a viscosity of about 0.89-2.0 cP through a constriction width of about 3-8 microns;
b) contacting the cell suspension with the complex of two or more molecules at a temperature of about 20-40C; and
c)(i) delivering higher levels of the complex into the immune cells…compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex; or
c)(ii) obtaining a higher number of viable cells when compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex.
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 [provisional application]. Thus, [provisional application] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
In the instant case, 62/277,858 recites a plurality of interwoven claims directed to individual parameter ranges, e.g. a temperature between 0C to 4C (claim 11), constriction width of 0.4um to 14um (claim 61), shear forces between 1kPa and 100kPa (claims 33-35), binding affinities between 1uM to 1pM (claims 4-5), ionic strengths between 50mM to 1000mM (claims 15-18), buffer/medium osmolarity values between 0 to 1000 mOsm/L (claims 24-25, 27-28), buffer/medium pH values ranging from 4.0 to 10.0 (claims 29-32). However, the originally filed claims, being so interwoven, do not provide sufficient blazemarks nor reasonably lead the ordinary artisan to the instantly recited combination of experimental parameters.
62/277,858 Examples 1-2 fail to disclose the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um. At best, it merely discloses the microfluidic channel has a constriction width of 4um and a channel length of 10 or 30 um. Instant Claim 1 is far broader in scope than 62/277,858 Examples 1-2.
The working examples fail to disclose the temperature, nor viscosity of the buffer/medium.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
PCT/US2017/013055 filed on January 11, 2017 and 16/068,631 filed on July 6, 2018, having the same specification as 62/277,858 suffer the same deficiencies.
See further discussion below under 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
Accordingly, the effective priority date of the instant application is granted as August 29, 2022, the effective 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.
Response to Arguments
Applicant argues that the amendment to independent Claim 1 renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive.
Instant recitation now requires three artisan action-taking steps, (a), (b), and (c), whereby (c) delivering/obtaining is different than, and in addition to (b) contacting. Applicant fails to point with particularity by page and line number where in the specifications of 62/277,858, PCT/US2017/013055, and instant application support the instant recitation step (c) in addition to step (b) is found.
Applicant argues that support for passing the immune cells through a constriction width of about 3-8um in a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP is found in 62/277,858 [0073, 75, 77] and the Examples.
Applicant’s argument(s) has been fully considered, but is not persuasive.
While 62/277,858 [0073] disclosed a physiological saline solution, it is silent to the parameters of constriction width of about 3-8um in a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP. There is nothing in [0073] that leads to the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um.
While 62/277,858 [0075] disclosed a viscosity of about 0.89-4.0 cP, it is silent to the parameters of constriction width of about 3-8um in a physiological saline solution or cell culture medium. There is nothing in [0075] that leads to the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um.
While 62/277,858 [0077] disclosed the microfluidic channel is configured to allow a cell to pass through a constriction, it is silent to the parameters of constriction width of about 3-8um in a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP. There is nothing in [0077] that leads to the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um.
62/277,858 Examples 1-2 fail to disclose the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um. At best, it merely discloses the microfluidic channel has a constriction width of 4um and a channel length of 10 or 30 um. Instant Claim 1 is far broader in scope than 62/277,858 Examples 1-2.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
Information Disclosure Statement
Applicant has filed an Information Disclosure Statement on November 10, 2025 that has been considered.
The information disclosure statement filed November 10, 2025 fails to comply with the provisions of 37 CFR 1.97, 1.98 and MPEP § 609 because 37 CFR 1.98(b) requires that each item of information in an IDS be identified properly. Each publication must be identified by publisher, author (if any), title, relevant pages of the publication, and date and place of publication. The date of publication supplied must include at least the month and year of publication, except that the year of publication (without the month) will be accepted if the applicant points out in the information disclosure statement that the year of publication is sufficiently earlier than the effective U.S. filing date and any foreign priority date so that the particular month of publication is not in issue.
See also MPEP 707.05(e) for electronic documents, including, but not limited to:
(D) reference to the unique Digital Object Identifier (DOI) number, or other unique identification number, if known.
NPL citations have been lined through for being defective of one or more requirements.
The signed and initialed PTO Forms 1449 are mailed with this action.
Specification
1. The prior objection to the specification is withdrawn in light of Applicant’s amendment to provide the trademark symbol.
Claim Objections
2. Claim 1 is objected to because of the following informalities:
Where a claim sets forth a plurality of elements or steps, each element or step of the claim should be separated by a line indentation, 37 CFR 1.75(i). See MPEP §608.01(m).
Step c(ii) should be separated from c(i) by line indentation.
Appropriate correction is required. See, for example, amended Claim 1 format currently lined through.
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.
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.
3. The prior rejection of Claims 61 and 64 are rejected 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.
4. Claims 1, 33, 36-37, 49, 61, 65, and 75-76 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 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium at a viscosity of about 0.89-2.0 cP through a constriction width of about 3-8 microns;
b) contacting the cell suspension with the complex of two or more molecules at a temperature of about 20-40C; and
c)(i) delivering higher levels of the complex into the immune cells…compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex; or
c)(ii) obtaining a higher number of viable cells when compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex.
As a first matter, instant recitation now requires three artisan action-taking steps, (a), (b), and (c), whereby (c) delivering/obtaining is different than, and in addition to (b) contacting. However, the specification fails to support a step (c) that is in addition to the step (b).
Rather, element (c) appears to instead be directed to the functional property(ies) achieved by having performed step (a) and (b).
As a second matter, c(i) is considered indefinite for failing to recite the delivering step(s) by which higher levels of the complex into the immune cells…compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex, thereby suffering from a gap in the nexus of method step(s)/functional property.
As a third matter, c(ii) is considered indefinite for failing to recite the obtaining step(s) by which a higher number of viable cells when compared to when the one or more of the two or more molecules are delivered into the immune cells not as a complex, thereby suffering from a gap in the nexus of method step(s)/functional property.
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
5. Claims 1, 33, 36-37, 49, 61, 65, and 75-76 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 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium at a viscosity of about 0.89-2.0 cP through a constriction width of about 3-8 um; and
b) contacting the cell suspension with the complex of two or more molecules at a temperature of about 20-40C,
whereby the constriction width of about 3-8um deforms the immune cell, causing a perturbation in the immune cell’s cell membrane, thereby allowing the complex to enter the immune cell.
Claim 1 has been amended in step (c)(i) to recite the functional property of ‘wherein the delivery of the complex of two or more molecules into the immune cell is higher compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Claim 1 has been amended in step (c)(ii) to recite the functional property of ‘wherein the method obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
The claim denotes that not all of having performed method step(s) of (a) and (b) using the recited condition parameters is/are able to achieve the functional property(ies) of:
c(i) delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex, and/or
c(ii) obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex.
Either the functional properties of c(i) and/or c(ii) is/are an inherent property, that naturally flows from, the method steps (a) and (b) positively recited, or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
The c(i) and/or c(ii) limitations merely states a functional characteristic without providing any indication about how the functional characteristic(s) is/are provided. The functional characteristic(s) do/does not follow from (is/are not an inherent property(ies) of) the structures and/or method step(s) experimental parameter(s) recited in steps (a) and/or (b), so it is unclear whether the claim requires some other structure to be added to the composition and/or some other change to the method step experimental parameter(s) are to necessarily and sufficiently provide the functional characteristic, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The claim is considered indefinite for failing to recite the structure(s) and/or method step(s) experimental parameter(s) that is/are necessary and sufficient to cause the recited functional language.
The complex comprises at least one polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality.
The breadth of the claim encompasses an enormously vast genus of structurally distinct first and second molecules of the complex, including an enormously vast genus of structurally undisclosed polypeptides, an enormously vast genus of structurally undisclosed nucleic acids, an enormously vast genus of structurally undisclosed lipids, an enormously vast genus of structurally undisclosed carbohydrates, an enormously vast genus of structurally undisclosed small molecules, and an enormously vast genus of structurally undisclosed metal-containing compounds.
The specification discloses the binding affinity may be about 1pM to about 1uM [0005].
While it is clear that the cell suspension is to be step (b) contacted with the complex at a temperature of about 20-40C, the claim does not require step (a) passing through a constriction at a temperature of about 20-40C. Thus, the breadth of step (a) is broader than step (b).
As discussed previously, instant specification discloses the temperature may be as low as 0C [0007].
The cell suspension may have:
an ionic strength between about 50mM to about 300mM [0008];
an osmolarity between about 100 mOsm/L to about 500 mOsm/L [0009];
a pH between about 5.5 to about 8.5 [0010];
a shear force of about 1kPa to about 100kPa [0011];
the inclusion of an enormously vast genus of structurally undisclosed cell culture mediums, buffers, salts, sugars, growth factors, animal derived products, bulking materials, detergents, surfactants, lubricants, vitamins, polypeptides, and/or an agent that impacts actin polymerization [0094]; and
the inclusion of a vast genus of detergents [0058] present at a concentration of about 0.1% (w/v) to about 10% (w/v) [0006].
Resina et al (Physico-Chemical Characteristics of Lipoplexes Influence Cell Uptake Mechanisms and Transfection Efficacy, PLoS ONE 4(6): e6058, 11 pages, June 2009; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C and 37C (e.g. pg 3, col. 1, Methods). Resina et al taught that the uptake mechanism is thermos-dependent because endocytosis is an energy-dependent and temperature-dependent process, and thus does not take place at 4C (e.g pg 5, col. 1). Thus, the ordinary artisan would immediately recognize that such membrane recovery from the deformation and fracturing caused by passing the cell suspension through a constriction width of 0.4um at temperatures of at least 0C to 4C will also not occur.
Rols et al (Temperature effects on electrotransfection of mammalian cells, Nucleic Acids Research 22(3): pg 540 only, 1994; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C, 21C and 37C, whereby the viability of the mammalian cells at 4C is about 10% less than the viability at 21C (45% vs 55%), and about 30% less than the viability at 37C (e.g. Table 2, 45% vs 75%).
Thus, the prior art contradicts the ability of the instantly recited method to achieve the recited functional properties.
The recitation implies a genus of undisclosed reference structures and method step experimental parameters from which “increased” is determined, thereby rendering the claim indefinite. A claim may be rendered indefinite by reference to an object that is variable. (MPEP §2173.05(b)).
The instant claim as a whole does not apprise one of ordinary skill in the art of its scope and, therefore, does not serve the notice function required by 35 U.S.C. 112, second paragraph, by providing clear warning to others as to what constitutes infringement of the patent.
Dependent claims are included in the basis of the rejection because they do not clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues that the amendment to independent Claim 1 renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Such amendment fails to satisfy 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, requirement.
Applicant fails to clarify the record as to whether or not the functional properties of c(i) and/or c(ii) is/are an inherent property, that naturally flows from, the method steps (a) and (b) positively recited, or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
If it is inherent, then it would be remedial for Applicant to state so, thereby clarifying the record.
If not inherent, then something of the structures and/or method step conditions must change.
When functional claim language is found indefinite, it typically lacks an adequate written description under §112(a), because an indefinite, unbounded functional limitation would cover a plurality of undisclosed structures and/or method steps of performing a function and indicate that the inventor has not provided sufficient disclosure to show possession of the invention. Thus, in most cases, a §112(b) rejection that is based on functional language having unclear (or no) claim boundaries should be accompanied by a rejection under §112(a) based on failure to provide a written description for the claim. See MPEP 2173.05(g).
New matter
6. Claim(s) 1, 33, 36-37, 49, 61, 65, and 75-76 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 Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The Examiner incorporates herein the above Priority discussion.
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.
Claim 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium at a viscosity of about 0.89-2.0 cP through a constriction width of about 3-8 um; and
b) contacting the cell suspension with the complex of two or more molecules at a temperature of about 20-40C,
whereby the constriction width of about 3-8um deforms the immune cell, causing a perturbation in the immune cell’s cell membrane, thereby allowing the complex to enter the immune cell.
Claim 1 has been amended in step (c)(i) to recite the functional property of ‘wherein the delivery of the complex of two or more molecules into the immune cell is higher compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Claim 1 has been amended in step (c)(ii) to recite the functional property of ‘wherein the method obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Clear support for the new limitation(s) cannot be found in the instant application or priority documents. Accordingly, the amendment(s) to Claim(s) 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 for support in Examples 1-5 of the instant application.
62/277,858 and instant Examples 1-2 fail to disclose the combination of the method step parameters of a physiological saline solution or cell culture medium having a viscosity of about 0.89-2.0 cP, and passing the immune cells through a constriction width of about 3-8um. At best, it merely discloses the microfluidic channel has a constriction width of 4um and a channel length of 10 or 30 um. Instant Claim 1 is far broader in scope than 62/277,858 Examples 1-2.
Examples 3-5 disclose contacting the cells with the complex prior to passing the cells through the constriction. Instant Claim 1 is far broader in scope than Examples 3-5.
Examples 3-5 disclose a microchannel having a constriction width of 7um and a length of 10 or 30um. Instant Claim 1 is far broader in scope than Examples 3-5.
Examples 3-5 fail to disclose temperature at which the cells were contacted with the complex.
Examples 3-5 fail to disclose temperature at which the cells were passed through the constriction.
Examples 3-5 fail to disclose the viscosity of the cell suspension medium during which the cells are passed through the constriction.
Applicant appears to be cherry-picking disparate, unconnected, method step parameter subgenera, and combinations and/or subcombinations thereof, which are not supported by the originally filed disclosure.
Alternatively, if Applicant believes that support for combination of method step parameters, as now recited in Claim(s) 1, is present and clearly envisaged in the instant application or earlier filed priority documents, applicant must, in responding to this Office Action, point out with particularity, where such support may be found.
Declarations and new references cannot demonstrate possession of a concept after the fact.
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.
The claim denotes that not all of the methods performing the positively recited step of “passing a cell suspension through a constriction” is/are able to achieve the functional property(ies) of “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex”.
The claim denotes that not all of the complexes comprising at least one polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality is/are able to achieve the functional property(ies) of “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex”.
Either the functional properties of c(i) and/or c(ii) is/are an inherent property, that naturally flows from, the method steps (a) and (b) positively recited, or it is not, and something of the method step(s) experimental parameter(s) and/or complexes themselves must change.
The c(i) and/or c(ii) limitations merely states a functional characteristic without providing any indication about how the functional characteristic(s) is/are provided.
The functional characteristic does not follow from (is not an inherent property of) the structures and/or method step experimental parameter(s) recited in the claim, so it is unclear whether the claim requires some other structure to be added to the composition and/or some other change to the method step experimental parameter(s) are to necessarily and sufficiently provide the functional characteristic, and thus the ordinary artisan would not know what modification(s) must be made in order to fulfill the instant recitation.
The claim is considered to lack adequate written description for failing to recite the additional structure(s) and/or additional method step(s) that is/are necessary and sufficient to cause the recited functional language.
The specification fails to disclose the additional structure(s) and/or additional method step(s) that is/are necessary and sufficient to cause the recited functional language.
The complex comprises at least one polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality.
While it is clear that the cell suspension is to be step (b) contacted with the complex at a temperature of about 20-40C, the claim does not require step (a) passing through a constriction at a temperature of about 20-40C. Thus, the breadth of step (a) is broader than step (b).
As discussed previously, instant specification discloses the temperature may be as low as 0C [0007].
The cell suspension may have:
an ionic strength between about 50mM to about 300mM [0008];
an osmolarity between about 100 mOsm/L to about 500 mOsm/L [0009];
a pH between about 5.5 to about 8.5 [0010];
a shear force of about 1kPa to about 100kPa [0011];
the inclusion of an enormously vast genus of structurally undisclosed cell culture mediums, buffers, salts, sugars, growth factors, animal derived products, bulking materials, detergents, surfactants, lubricants, vitamins, polypeptides, and/or an agent that impacts actin polymerization [0094]; and
the inclusion of a vast genus of detergents [0058] present at a concentration of about 0.1% (w/v) to about 10% (w/v) [0006].
The claims fail to recite, and the specification fails to disclose, a first method delivering a polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality, and it’s corresponding method step working parameters, to wit, temperature, ionic strength, osmolarity, pH, shear force, presence and/or absence of one or more different additional ingredients, including but not limited to detergents, individually and/or in combination and/or subcombinations thereof, respectively, that is necessarily and predictably achieves “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex” as opposed to a second method delivering a polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality, and it’s corresponding method step working parameters, to wit, temperature, ionic strength, osmolarity, pH, shear force, presence and/or absence of one or more different additional ingredients, including but not limited to detergents, individually and/or in combination and/or subcombinations thereof, respectively, that does not achieve “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex”.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first method delivering a polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality, and it’s corresponding method step working parameters, to wit, temperature, ionic strength, osmolarity, pH, shear force, presence and/or absence of one or more different additional ingredients, including but not limited to detergents, individually and/or in combination and/or subcombinations thereof, respectively, that does not achieve “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex” into a second method delivering a polypeptide recited at a high level of generality non-covalently associated with a second molecule recited at a high level of generality, and it’s corresponding method step working parameters, to wit, temperature, ionic strength, osmolarity, pH, shear force, presence and/or absence of one or more different additional ingredients, including but not limited to detergents, individually and/or in combination and/or subcombinations thereof, respectively, that now necessarily and predictably achieves “delivery of the complex of two or more molecules into the immune cell is increased compared to when one or more of the two or more molecules are delivered into the immune cell not as a complex”.
Sharei et al (WO 13/059343; of record in parent application 16/068,631) is considered relevant prior art for having disclosed a method and a system for delivering a complex of two or more molecules into a cell, the method comprising the step of passing a cell suspension through a constriction,
wherein said constriction deforms the cell, thereby causing a perturbation of the cell such that the complex of molecules enters the cell, and
wherein said cell suspension is contacted with the complex of molecules (Abstract: Figure 1b).
Sharei et al disclosed wherein the complex of molecules comprises one or more polypeptides (pg 8, line 6, “proteins”), e.g. a complex of two or more molecules may comprise, e.g. fluorescein covalently conjugated BSA (pg 46, lines 24-28).
Sharei et al disclosed a working example using DNA-wrapped carbon nanotubes (pg 50, lines 24-25), whereby those of ordinary skill in the art previously recognized that the DNA encapsulates the carbon nanotubes non-covalently. Thus, Applicant himself had previously successfully demonstrated the use of the instantly claimed microfluidic platform to introduce macromolecular complexes comprising at least two, structurally distinct molecules non-covalently complexed with each other into the target host cells.
While Sharei et al disclosed that the method may be used to deliver known amounts of DNA sequences together with known amounts of enzymes (syn. polypeptides) that enhance DNA recombination (pg 8, lines 25-26), known amounts of RNA silencing molecules with known amounts of Dicer (syn. polypeptide) molecules (pg 9, lines 2-4), co-delivery of two molecules (dextran and apolipoprotein (syn. polypeptide)) able to enter the same host cell per the method (pg 46, lines 15-19; Example 2), and delivery of four transcription factors (syn. first, second, third, fourth polypeptides) in to the same host cell (pg 51, lines 23-24; pg 64, lines 29-30), Sharei et al do not disclose ipsis verbis that the at least first polypeptide in each working example is/are complexed with the other molecule(s), let alone complexed by non-covalent bonds.
While Sharei et al disclosed the method may be used to introduce individual molecules or complexed molecules into the target cells, Sharei et al is silent as to what modifications to the method comprising the step of passing a cell suspension through a constriction are required in order to achieve the instantly recited functional property of “…increased compared to a corresponding method…”.
The breadth of the claim encompasses cell suspensions at or near freezing temperatures (syn. frozen solid), 0C. Thus, the ordinary artisan would immediately recognize that the cellular cytoplasm and membrane will be fractured upon passing the cell suspension through a constriction width of 3-8um because of the deformation and perturbation.
Resina et al (Physico-Chemical Characteristics of Lipoplexes Influence Cell Uptake Mechanisms and Transfection Efficacy, PLoS ONE 4(6): e6058, 11 pages, June 2009; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C and 37C (e.g. pg 3, col. 1, Methods). Resina et al taught that the uptake mechanism is thermos-dependent because endocytosis is an energy-dependent and temperature-dependent process, and thus does not take place at 4C (e.g pg 5, col. 1). Thus, the ordinary artisan would immediately recognize that such membrane recovery from the deformation and fracturing caused by passing the cell suspension through a constriction width of 3-8um at temperatures of at least 0C to 4C will also not occur.
Rols et al (Temperature effects on electrotransfection of mammalian cells, Nucleic Acids Research 22(3): pg 540 only, 1994; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C, 21C and 37C, whereby the viability of the mammalian cells at 4C is about 10% less than the viability at 21C (45% vs 55%), and about 30% less than the viability at 37C (e.g. Table 2, 45% vs 75%).
Thus, the prior art contradicts the ability of the instantly recited method to achieve the recited functional properties.
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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues that the amendment to independent Claim 1 renders the prior rejection moot.
Applicant’s argument(s) has been fully considered, but is not persuasive. Applicant fails to point out with particularity where the instantly recited combination of method parameters are disclosed in the specification.
7. Claims 1, 33, 36-37, 49, 61, 65, and 75-76 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.
Claim 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium at a viscosity of about 0.89-2.0 cP through a constriction width of about 3-8 um; and
b) contacting the cell suspension with the complex of two or more molecules at a temperature of about 20-40C,
whereby the constriction width of about 3-8um deforms the immune cell, causing a perturbation in the immune cell’s cell membrane, thereby allowing the complex to enter the immune cell.
Claim 1 has been amended in step (c)(i) to recite the functional property of ‘wherein the delivery of the complex of two or more molecules into the immune cell is higher compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Claim 1 has been amended in step (c)(ii) to recite the functional property of ‘wherein the method obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The Examiner incorporates herein the above Priority discussion.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejection.
The prior art contradicts the ability of the instantly recited method to achieve the recited functional properties.
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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
8. Claim(s) 1, 33, 36-37, 49, 61, 65, and 75-76 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.
Claim 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium [parameter 2] at a viscosity of about 0.89-2.0 cP [parameter 3] through a constriction width of about 3-8 um [parameter 5]; and
b) contacting the cell suspension with the complex of two or more molecules comprising at least one polypeptide [parameter 1] associated by a non-covalent interaction at a temperature of about 20-40C [parameter 4],
whereby the constriction width of about 3-8um deforms the immune cell, causing a perturbation in the immune cell’s cell membrane, thereby allowing the complex to enter the immune cell.
Claim 1 has been amended in step (c)(i) to recite the functional property of ‘wherein the delivery of the complex of two or more molecules into the immune cell is higher compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Claim 1 has been amended in step (c)(ii) to recite the functional property of ‘wherein the method obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The Examiner incorporates herein the above Priority discussion.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, rejections.
The claims are considered to lack adequate written description for the recited combination of experimental parameters.
There is also a lack of adequate written description regarding the nexus of the enormous genus of structurally and functionally undisclosed physiological saline solutions and/or cell culture mediums [structures] having the functional properties of a viscosity between 0.89 centipoise (cP) to 2.0cP at a temperature of about 0C to 40C [functions].
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).
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 [provisional application]. Thus, [provisional application] do not provide sufficient written description support for the sub-genus of challenged claim 1.” Decision at *10.
In the instant case, 62/277,858 recites a plurality of interwoven claims directed to individual parameter ranges, e.g. a temperature between 0C to 4C (claim 11), constriction width of 0.4um to 14um (claim 61), shear forces between 1kPa and 100kPa (claims 33-35), binding affinities between 1uM to 1pM (claims 4-5), ionic strengths between 50mM to 1000mM (claims 15-18), buffer/medium osmolarity values between 0 to 1000 mOsm/L (claims 24-25, 27-28), buffer/medium pH values ranging from 4.0 to 10.0 (claims 29-32). However, the originally filed claims, being so interwoven, do not provide sufficient blazemarks nor reasonably lead the ordinary artisan to the instantly recited combination of experimental parameters.
The 62/277,858 suffers similar deficiencies.
At best, the working examples (pg 48, [0182]; pg 49, [0185]) disclose a constriction width of 4um.
However, the working examples fail to disclose the temperature, nor viscosity of the buffer/medium.
The breadth of the claim encompasses cell suspensions at or near freezing temperatures (syn. frozen solid), 0C. Thus, the ordinary artisan would immediately recognize that the cellular cytoplasm and membrane will be fractured upon passing the cell suspension through a constriction width of 0.4um because of the deformation and perturbation.
Resina et al (Physico-Chemical Characteristics of Lipoplexes Influence Cell Uptake Mechanisms and Transfection Efficacy, PLoS ONE 4(6): e6058, 11 pages, June 2009; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C and 37C (e.g. pg 3, col. 1, Methods). Resina et al taught that the uptake mechanism is thermos-dependent because endocytosis is an energy-dependent and temperature-dependent process, and thus does not take place at 4C (e.g pg 5, col. 1). Thus, the ordinary artisan would immediately recognize that such membrane recovery from the deformation and fracturing caused by passing the cell suspension through a constriction width of 0.4um at temperatures of at least 0C to 4C will also not occur.
Rols et al (Temperature effects on electrotransfection of mammalian cells, Nucleic Acids Research 22(3): pg 540 only, 1994; of record) is considered relevant prior art for having taught a method of transfecting complexes into a target mammalian host cell at temperatures of 4C, 21C and 37C, whereby the viability of the mammalian cells at 4C is about 10% less than the viability at 21C (45% vs 55%), and about 30% less than the viability at 37C (e.g. Table 2, 45% vs 75%).
Thus, the prior art contradicts the ability of the instantly recited method to achieve the recited functional properties.
The claimed buffer or culture medium [parameter 2] is recited at a high level of generality, and:
may comprise an enormously vast genus of chemically distinct compounds, e.g. sugars, salts, growth factors, animal-derived products, bulking materials, surfactants, lubricants, vitamins, etc… [0094];
may comprise a broad range of pH values, e.g. 4.0 to 10 [0010];
may comprise a broad range of osmolarity values, e.g. 0 mOsm/L to 500 mOsm/L [0009]; and/or
may comprise a broad range of ionic strengths, e.g. 0mM to 1000mM [0008].
Thus, the breadth of the claimed buffer or culture medium encompasses an infinite genus of structurally undisclosed formulations.
Tirtaatmadja et al (Rheology of dextran solutions, J. Non-Newtonian Fluid Mech. 97: 295–301, 2001; of record) is considered relevant prior art for having taught that measuring intrinsic viscosity varies amongst different researchers, as it is dependent the temperature and nature of the solvent (syn. “buffer or culture medium”), as well as the molecular weight of the dextran and degree of branching (e.g. pg 296, para 1).
The working example discloses co-delivering the complexes in a medium comprising OptiMEM (e.g. [0206]).
Poon (Measuring the density and viscosity of culture media for optimized computational fluid dynamics analysis of in vitro devices, bioRxiv doi.org/10.1101/2020.08.25.266221, 15 pages, available online August 25, 2020; of record) is considered relevant art for having taught that the viscosity of culture media is expected to be denser and more viscous than water because the higher solute content comprising sugars, inorganic salts, and serum proteins (e.g. pg 2). The presence of additional metabolites, growth factors, and proteins will naturally increase viscosity.
Poon taught culture medium viscosity values for DMEM and RPMI-1640 culture mediums, at 0%, 5%, 10%, and 20% serum, measured at a temperature of 37C, to range from 0.73 to 1.09 mPa.s (e.g. Table 2), which is an estimated equivalence of 0.73cP to 1.09cP (1cP = 1mPa.s). Even water, at 37C has a viscosity of 0.66 mPa.s (syn. 0.66cP).
(www.unitconverters.net/viscosity-dynamic/centipoise-to-pascal-second.htm; last visited June 10, 2025; of record).
The claims fail to recite, and the specification fails to disclose, a first physiological saline solution having a viscosity of 0.89cP, as opposed to a second physiological saline solution that has a viscosity of 2.0cP.
The claims fail to recite, and the specification fails to disclose, a first cell culture medium having a viscosity of 0.89cP, as opposed to a second cell culture medium that has a viscosity of 2.0cP.
As discussed above, while it is clear that the cell suspension is to be step (b) contacted with the complex at a temperature of about 20-40C, the claim does not require step (a) passing through a constriction at a temperature of about 20-40C. Thus, the breadth of step (a) is broader than step (b).
As discussed previously, instant specification discloses the temperature may be as low as 0C [0007].
The claims fail to recite, and the specification fails to disclose, a first physiological saline solution having a viscosity of 0.89cP at 0C, as opposed to a second physiological saline solution that has a viscosity of 2.0cP at 0C, for example.
The claims fail to recite, and the specification fails to disclose, a first physiological saline solution having a viscosity of 0.89cP at 4C, but not at 8C, 10C, 12C, 16C, 18C, etc…, as opposed to a second physiological saline solution that has a viscosity of 2.0cP at 4C, but not at 8C, 10C, 12C, 16C, 18C, etc…, for example.
The claims fail to recite, and the specification fails to disclose, a first cell culture medium having a viscosity of 0.89cP at 40C, but not at 8C, 10C, 12C, 16C, 18C, etc…, as opposed to a second cell culture medium that has a viscosity of 2.0cP at 40C, but not at 8C, 10C, 12C, 16C, 18C, etc…, for example.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
Examples 1-5 disclose contacting the cells with the complex prior to passing the cells through the constriction. Instant Claim 1 is far broader in scope than Examples 3-5.
Examples 3-5 disclose a microchannel having a constriction width of 7um and a length of 10 or 30um. Instant Claim 1 is far broader in scope than Examples 3-5.
Examples 3-5 fail to disclose temperature at which the cells were contacted with the complex.
Examples 3-5 fail to disclose temperature at which the cells were passed through the constriction.
Examples 3-5 fail to disclose the viscosity of the cell suspension medium during which the cells are passed through the constriction.
The claims fail to recite, and the specification fails to disclose, the structure/function nexus of the buffer/medium formulary [structure; parameter 2] and its corresponding viscosity [function; parameter 3], let alone the function/function nexus of the viscosity [function; parameter 3] at the corresponding temperature [function; parameter 4].
The claims fail to recite, and the specification fails to disclose, a first physiological saline solution and/or cell culture medium having a 0.92 cP viscosity at 0C, as opposed to a second physiological saline solution and/or cell culture medium having a viscosity of 1.63 cP at a temperature of 32C, for example.
The claims fail to recite, and the specification fails to disclose, a first physiological saline solution and/or cell culture medium that does not have a 3 cP viscosity at 40C, as opposed to a second physiological saline solution and/or cell culture medium that necessarily and predictably has a 3 cP viscosity at 40C, for example.
The claims fail to recite, and the specification fails to disclose, how to transform or otherwise modify a first physiological saline solution and/or cell culture medium that does not have a 2.5 cP viscosity at 25C into a second physiological saline solution and/or cell culture medium that now, necessarily and predictably has a 2.5 cP viscosity at 25C, for example.
The breadth of the claimed polypeptide present in the complex of two or more molecules comprising at least one polypeptide that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds (e.g. [0069]) [parameter 1] is an enormously vast genus, whereby the specification discloses the protein or polypeptide is “not limited to a minimum length” and may comprise one or more amino acid substitutions, insertions, and/or deletions [0050].
Tiessen et al (Mathematical modeling and comparison of protein size distribution in different plant, animal, fungal and microbial species reveals a negative correlation between protein size and protein number, thus providing insight into the evolution of proteomes, BMC Research Notes 5: e85, 23 pages, www.biomedcentral.com/1756-0500/5/85; available online 2012; of record) is considered relevant prior art for having taught that the average eukaryotic protein is about 472 amino acids in length (Abstract).
20^472 is an infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds (e.g. [0069]).
(www.calculator.net/exponent-calculator.html; last visited June 9, 2025; of record)
A “representative number of species” means that the species which are adequately described are representative of the entire genus. Thus, when there is substantial variation within the genus, one must describe a sufficient variety of species to reflect the variation within the genus. See AbbVie Deutschland GmbH & Co., KG v. Janssen Biotech, Inc., 759 F.3d 1285, 1300, 111 USPQ2d 1780, 1790 (Fed. Cir. 2014) (Claims directed to a functionally defined genus of antibodies were not supported by a disclosure that “only describe[d] one type of structurally similar antibodies” that “are not representative of the full variety or scope of the genus.”).
Noelle v. Lederman, 355 F.3d 1343, 1350, 69 USPQ2d 1508, 1514 (Fed. Cir. 2004) (Fed. Cir. 2004) (“[A] patentee of a biotechnological invention cannot necessarily claim a genus after only describing a limited number of species because there may be unpredictability in the results obtained from species other than those specifically enumerated.”). “A patentee will not be deemed to have invented species sufficient to constitute the genus by virtue of having disclosed a single species when … the evidence indicates ordinary artisans could not predict the operability in the invention of any species other than the one disclosed.” In re Curtis, 354 F.3d 1347, 1358, 69 USPQ2d 1274, 1282 (Fed. Cir. 2004)
The Federal Circuit has explained that a specification cannot always support expansive claim language and satisfy the requirements of 35 U.S.C. 112 “merely by clearly describing one embodiment of the thing claimed.” LizardTech v. Earth Resource Mapping, Inc., 424 F.3d 1336, 1346, 76 USPQ2d 1731, 1733 (Fed. Cir. 2005).
For inventions in an unpredictable art, adequate written description of a genus which embraces widely variant species cannot be achieved by disclosing only one species within the genus. See, e.g., Eli Lilly, 119 F.3d at 1568, 43 USPQ2d at 1406. Instead, the disclosure must adequately reflect the structural diversity of the claimed genus, either through the disclosure of sufficient species that are “representative of the full variety or scope of the genus,” or by the establishment of “a reasonable structure-function correlation.” Such correlations may be established “by the inventor as described in the specification,” or they may be “known in the art at the time of the filing date.” See AbbVie, 759 F.3d at 1300-01, 111 USPQ2d 1780, 1790-91 (Fed. Cir. 2014)
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 cells are to be placed in an infinite genus of structurally unrecited and undisclosed suspension buffers or culture mediums does not tell you anything at all about the corresponding viscosity value of said infinite genus of structurally unrecited and undisclosed suspension buffers or culture mediums, let alone the corresponding viscosity value at corresponding temperature(s) ranging from freezing, 0C, to 40C.
Knowing that the initial complex is to comprise at least one polypeptide does not tell you anything at all about the infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds, whereby said infinite genus of complexes are to be introduced into the immune cell upon passing the immune cell through a constriction width of 0.4um, and whereby the viability of the immune cell after delivery of the complex is increased compared to when the polypeptide and second molecule is delivered to the immune not as a complex.
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 an entire universe of structurally undisclosed buffer and culture medium formularies described only using functional language “a viscosity ranging between about 0.89cP and 4.0cP”.
the record reflects that Applicant seeks to claim an entire universe of structurally undisclosed complexes comprising infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds.
“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.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
The instant specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which they fail to disclose.
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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
9. Claims 1, 33, 36-37, 49, 61, 65, and 75-76 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.
Claim 1 has been amended to recite a method of delivering a complex of two or more molecules into the immune cell comprising the step(s) of:
a) passing a cell suspension of immune cells in a physiological saline solution or a cell culture medium [parameter 2] at a viscosity of about 0.89-2.0 cP [parameter 3] through a constriction width of about 3-8 um [parameter 5]; and
b) contacting the cell suspension with the complex of two or more molecules comprising at least one polypeptide [parameter 1] associated by a non-covalent interaction at a temperature of about 20-40C [parameter 4],
whereby the constriction width of about 3-8um deforms the immune cell, causing a perturbation in the immune cell’s cell membrane, thereby allowing the complex to enter the immune cell.
Claim 1 has been amended in step (c)(i) to recite the functional property of ‘wherein the delivery of the complex of two or more molecules into the immune cell is higher compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
Claim 1 has been amended in step (c)(ii) to recite the functional property of ‘wherein the method obtains a higher number of viable cells when delivering the complex, as compared to when the one or more of the two or more molecules are delivered into the immune cell not as a complex’.
The Examiner incorporates herein the above 35 U.S.C. 112(b) or 35 U.S.C. 112 (pre-AIA ), second paragraph, rejections.
The Examiner incorporates herein the above Priority discussion.
The Examiner incorporates herein the above 35 U.S.C. 112(a) or 35 U.S.C. 112 (pre-AIA ), first paragraph, 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 cells are to be placed in an infinite genus of structurally unrecited and undisclosed suspension buffers or culture mediums does not tell you anything at all about the corresponding viscosity value of said infinite genus of structurally unrecited and undisclosed suspension buffers or culture mediums, let alone the corresponding viscosity value at corresponding temperature(s) ranging from freezing, 0C, to 40C.
Knowing that the initial complex is to comprise at least one polypeptide does not tell you anything at all about the infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds, whereby said infinite genus of complexes are to be introduced into the immune cell upon passing the immune cell through a constriction width of 0.4um, and whereby the viability of the immune cell after delivery of the complex is increased compared to when the polypeptide and second molecule is delivered to the immune not as a complex.
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 an entire universe of structurally undisclosed buffer and culture medium formularies described only using functional language “a viscosity ranging between about 0.89cP and 4.0cP”.
the record reflects that Applicant seeks to claim an entire universe of structurally undisclosed complexes comprising infinite genus of structurally undisclosed polypeptides that are to be complexed non-covalently with an infinite genus of structurally undisclosed nucleic acids, other polypeptides, other peptides, lipids, carbohydrates, small molecules, and/or metal-containing compounds.
“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.
While the working example discloses that the complexing conditions, including complex concentration, solution osmolarity, salt concentration, temperature, pH, serum and surfactant content, and viscosity are optimized [0206], the specification fails to disclose what these optimized parameter values are.
The instant specification fails to make up for the deficiencies of the global scientific community.
Applicant is essentially requiring the ordinary artisans to discover for themselves that which they fail to disclose.
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 clarify the nature of the corresponding structure that is necessary and sufficient to cause the recited functional language of the independent claim.
Response to Arguments
Applicant argues secondary consideration of having introduced into pluripotent stem cells a complex of an anti-Cas antibody non-covalently associated with a Cas9/sgRNA ribonucleoprotein complex in a solution having a viscosity ranging from 1-1.8 cP, and passing the cells/antibody-RNP complex through a constriction of about 6um, or having introduced into T cells a complex of an anti-Cas antibody non-covalently associated with a Cas9/sgRNA ribonucleoprotein complex in a solution having a viscosity ranging from 1-1.8 cP, and passing the cells/antibody-RNP complex through a constriction of about 4um (Remarks Made in Amendment, pg 15).
Applicant’s argument(s) has been fully considered, but is not persuasive.
Applicant’s asserted secondary considerations, which fail to disclose:
i) the physiological saline solution formulary and temperature(s) during the (b) contacting step;
ii) the temperature(s) (a) passing the cell suspension through a constriction; and
iii) whether the contacting step is performed before, during, or after the step (a) passing the cell suspension through a constriction.
Applicant’s secondary considerations fail to disclose the method step/functional property nexus of (c)(i) and/or (c)(ii).
Instant claims are far broader in scope than Applicant’s asserted secondary considerations, e.g. the type of complex of the two or more molecules.
At best, Examples 1-5 disclose contacting the cells with the complex prior to passing the cells through the constriction. Instant Claim 1 is far broader in scope than Examples 3-5.
Conclusion
10. No claims are 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 KEVIN K. HILL whose telephone number is (571)272-8036. The examiner can normally be reached 12pm-8pm EST.
Examiner interviews are available via telephone, in-person, and video conferencing using a USPTO supplied web-based collaboration tool. To schedule an interview, applicant is encouraged to use the USPTO Automated Interview Request (AIR) at http://www.uspto.gov/interviewpractice.
If attempts to reach the examiner by telephone are unsuccessful, the examiner’s supervisor, Tracy Vivlemore can be reached at 571-272-2914. The fax phone number for the organization where this application or proceeding is assigned is 571-273-8300.
Information regarding the status of published or unpublished applications may be obtained from Patent Center. Unpublished application information in Patent Center is available to registered users. To file and manage patent submissions in Patent Center, visit: https://patentcenter.uspto.gov. Visit https://www.uspto.gov/patents/apply/patent-center for more information about Patent Center and https://www.uspto.gov/patents/docx for information about filing in DOCX format. For additional questions, contact the Electronic Business Center (EBC) at 866-217-9197 (toll-free). If you would like assistance from a USPTO Customer Service Representative, call 800-786-9199 (IN USA OR CANADA) or 571-272-1000.
KEVIN K. HILL
Examiner
Art Unit 1638
/KEVIN K HILL/Primary Examiner, Art Unit 1638