Sec Form 3 Filing - ORBIMED ADVISORS LLC @ Upstream Bio, Inc. - 2024-10-10

FORM 3 Check this box if no longer subject to Section 16. Form 4 or Form 5 obligations may continue. See Instruction 1(b).

UNITED STATES SECURITIES AND EXCHANGE COMMISSION Washington, D.C. 20549 STATEMENT OF CHANGES IN BENEFICIAL OWNERSHIP Filed pursuant to Section 16(a) of the Securities Exchange Act of 1934, Section 17(a) of the Public Utility Holding Company Act of 1935 or Section 30(h) of the Investment Company Act of 1940

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1. Name and Address of Reporting Person ORBIMED ADVISORS LLC 2. Issuer Name and Ticker or Trading Symbol Upstream Bio, Inc. [ UPB] 5. Relationship of Reporting Person(s) to Issuer (Check all applicable) X __ Director X __ 10% Owner _____ Officer (give title below) _____ Other (specify below) (Last) (First) (Middle) 601 LEXINGTON AVENUE, 54TH FLOOR 3. Date of Earliest Transaction (MM/DD/YY) 10/10/2024 (Street) NEW YORK, NY10022 4. If Amendment, Date Original Filed (MM/DD/YY) 6. Individual or Joint/Group Filing (Check Applicable Line) _____ Form filed by One Reporting Person __ X __ Form filed by More than One Reporting Person (City) (State) (Zip)

Table I - Non-Derivative Securities Acquired, Disposed of, or Beneficially Owned 1.Title of Security (Instr. 3) 2. Transaction Date (MM/DD/YY) 2A. Deemed Execution Date, if any (MM/DD/YY) 3. Transaction Code (Instr. 8) 4. Securities Acquired (A) or Disposed of (D) (Instr. 3, 4 and 5) 5. Amount of Securities Beneficially Owned Following Reported Transaction(s) (Instr. 3 and 4) 6. Ownership Form: Direct (D) or Indirect (I) (Instr. 4) 7. Nature of Indirect Beneficial Ownership (Instr. 4) Code V Amount (A) or (D) Price Common Stock 251,760 I By OrbiMed Israel Partners II, L.P. ( 1 ) ( 2 ) Common Stock 1,007,040 I By OrbiMed Private Investments VIII, LP ( 2 ) ( 3 )

Table II - Derivative Securities Acquired, Disposed of, or Beneficially Owned ( e.g. , puts, calls, warrants, options, convertible securities) 1. Title of Derivative Security (Instr. 3) 2. Conversion or Exercise Price of Derivative Security 3. Transaction Date (MM/DD/YY) 3A. Deemed Execution Date, if any (MM/DD/YY) 4. Transaction Code (Instr. 8) 5. Number of Derivative Securities Acquired (A) or Disposed of (D) (Instr. 3, 4, and 5) 6. Date Exercisable and Expiration Date (MM/DD/YY) 7. Title and Amount of Underlying Securities (Instr. 3 and 4) 8. Price of Derivative Security (Instr. 5) 9. Number of Derivative Securities Beneficially Owned Following Reported Transaction(s) (Instr. 4) 10. Ownership Form of Derivative Security: Direct (D) or Indirect (I) (Instr. 4) 11. Nature of Indirect Beneficial Ownership (Instr. 4) Code V (A) (D) Date Exercisable Expiration Date Title Amount or Number of Shares Series A redeemable convertible prefer red stock ( 4 ) ( 4 ) ( 4 ) Common Stock 524,500 I By OrbiMed Israel Partners II, L.P. ( 1 ) ( 2 ) Series A redeemable convertible preferred stock ( 4 ) ( 4 ) ( 4 ) Common Stock 2,098,000 I By OrbiMed Private Investments VIII, LP ( 2 ) ( 3 ) Series B redeemable convertible preferred stock ( 4 ) ( 4 ) ( 4 ) Common Stock 197,456 I By OrbiMed Israel Partners II, L.P. ( 1 ) ( 2 ) Series B redeemable convertible preferred stock ( 4 ) ( 4 ) ( 4 ) Common Stock 789,833 I By OrbiMed Private Investments VIII, LP ( 2 ) ( 3 )

Reporting Owners Reporting Owner Name / Address Relationships Director 10% Owner Officer Other ORBIMED ADVISORS LLC 601 LEXINGTON AVENUE 54TH FLOOR NEW YORK, NY10022 X X OrbiMed Capital GP VIII LLC 601 LEXINGTON AVENUE 54TH FLOOR NEW YORK, NY10022 X X OrbiMed Advisors Israel II Ltd 601 LEXINGTON AVENUE 54TH FLOOR NEW YORK, NY10022 X X OrbiMed Israel GP II, L.P. 601 LEXINGTON AVENUE 54TH FLOOR NEW YORK, NY10022 X X Signatures /s/ Carl L. Gordon, Member of OrbiMed Advisors LLC 10/10/2024 Signature of Reporting Person Date /s/ Carl L. Gordon, Member of OrbiMed Capital GP VIII LLC 10/10/2024 Signature of Reporting Person Date /s/ Carl L. Gordon, Director of OrbiMed Advisors Israel II Ltd. 10/10/2024 Signature of Reporting Person Date /s/ Carl L. Gordon, Director of OrbiMed Israel GP II, L.P. 10/10/2024 Signature of Reporting Person Date

Explanation of Responses:

( 1 )Shares held by OrbiMed Israel Partners II, L.P. ("OIP II"). OrbiMed Israel GP II, L.P. ("OrbiMed Israel GP II") is the general partner of OIP II, and OrbiMed Advisors Israel II Limited ("OrbiMed Israel II") is the general partner of OrbiMed Israel GP II. By virtue of such relationships, OrbiMed Israel GP II and OrbiMed Israel II may be deemed to have voting power and investment power over the securities held by OIP II and as a result, may be deemed to have beneficial ownership over such securities. OrbiMed Israel II exercises this investment and voting power through a management committee comprised of Carl L. Gordon, David P. Bonita, and the Erez Chimovits, each of whom disclaims beneficial ownership of the shares held by OIP II. ( 2 )Each of the OrbiMed Israel GP II, OrbiMed Israel II, OrbiMed Capital GP VIII LLC ("GP VIII"), and OrbiMed Advisors LLC ("OrbiMed Advisors") disclaims beneficial ownership of the securities reported herein for purposes of Rule 16a-1(a) under the Securities Exchange Act of 1934, as amended (the "Exchange Act"), except to the extent of his or its pecuniary interest therein, if any. The Reporting Persons have designated a representative, Erez Chimovits, to serve on the Issuer's board of directors. This report shall not be deemed an admission that any such entity or person is a beneficial owner of such securities for purposes of Section 16 of the Exchange Act, or for any other purpose. ( 3 )Shares held by OrbiMed Private Investments VIII, LP ("OPI VIII"). GP VIII is the general partner of OPI VIII, and OrbiMed Advisors is the managing member of GP VIII. By virtue of such relationships, GP VIII and OrbiMed Advisors may be deemed to have voting power and investment power over the securities held by OPI VIII and as a result, may be deemed to have beneficial ownership over such securities. OrbiMed Advisors exercises voting and investment power through a management committee comprised of Carl L. Gordon, Sven H. Borho, and W. Carter Neild, each of whom disclaims beneficial ownership of the shares held by OPI VIII. ( 4 )Each share of Series A redeemable convertible preferred stock and Series B redeemable convertible preferred stock (collectively, the "Preferred Stock") is convertible into Common Stock on a 1.049-for-one basis at the option of the holder, and will convert automatically upon closing of the Issuer's initial public offering into the number of shares shown in column 3 without payment of consideration. The Preferred Stock has no expiration date.

Reminder: Report on a separate line for each class of securities beneficially owned directly or indirectly.

* If the form is filed by more than one reporting person, see Instruction 4(b)(v).

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